Mevrometostat

 

Mevrometostat

CAS 1844849-10-0

MF C22H24Cl2N2O5 MW467.3 g/mol

5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one

5,8-dichloro-7-[(R)-methoxy(oxetan-3-yl)methyl]-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-
dihydroisoquinolin-1(2H)-one
enhancer of zeste homolog 2 (EZH2) inhibitor, antineoplastic, PF-06821497, PF 06821497, S4L4MM20B6

Mevrometostat (development code PF-06821497) is an investigational anticancer drug that functions as a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2).^[1][2] Currently under development by Pfizer, mevrometostat is being investigated primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in combination with enzalutamide.

PF-06821497 is under investigation in clinical trial NCT03460977 (PF-06821497 Treatment Of Relapsed/Refractory SCLC, Castration Resistant Prostate Cancer, and Follicular Lymphoma).

Mevrometostat is an orally available selective inhibitor of the histone lysine methyltransferase (HMT) enhancer of zeste homolog 2 (EZH2), with potential antineoplastic activity. Upon oral administration, mevrometostat selectively targets, binds to and inhibits the activity of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 on lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased proliferation of EZH2-expressing cancer cells. EZH2, an HMT class enzyme and the catalytic subunit of the polycomb repressive complex 2 (PRC2), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation; its expression is correlated with tumor initiation, progression, stem cell self-renewal, migration and angiogenesis.

MEVROMETOSTAT is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Synthesis

LAST STEP CONDITIONS

METHYL IODIDE REAGENT, Tetrahydrofuran , Potassium tert-butoxide
NEXT Hydrogen, Platinum dioxide,

SYN

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)Publication Name: Journal of Medicinal ChemistryPublication Date: 2017-12-27PMID: 29211475DOI: 10.1021/acs.jmedchem.7b01375

compound 23a [PMID: 29211475]

5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-
methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one (23a) and 5,8-dichloro-2-[(4-
methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(S)-methoxy(oxetan-3-yl)methyl]-
3,4-dihydroisoquinolin-1(2H)-one (23b)

Multiple batches of (±)-5,8-dichloro-2-[(4-methoxy-6-
methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[methoxy-
(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one 40
were combined (140 mg total), and the enantiomers separated
by preparative chiral SFC [Column: (R,R)Whelk O1
250mm*30mm,5µ; mobile phase: EtOH; wavelength: 220
nm] to give, after lyophilization, 23a (50.3 mg, 36%) as a
white solid, and 23b (22.8 mg, 16%) as a white solid. A
small-molecule X-Ray crystal structure of 23a showed it to
have absolute (R) stereochemistry. A small-molecule X-Ray crystal structure of 23b confirmed
the expected absolute (S) stereochemistry.
5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-
methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one (23a). After chiral SFC and
lyophilization, 23a (50.3 mg, 36%) was obtained as a white solid. LCMS m/z 489 [M+Na]+; 1H
NMR (400 MHz, CDCl3) δ 12.34 (br s, 1H), 7.49 (s, 1H), 5.93 (s, 1H), 5.05 (d, J=6.0 Hz, 1H),
4.78-4.61 (m, 6H), 3.88 (s, 3H), 3.50-3.48 (m, 2H), 3.38-3.37 (m, 1H), 3.31 (s, 3H), 2.94 (t,
J=6.2 Hz, 2H), 2.35 (s, 3H). [α]D
22 +67.7° (c 0.1, MeOH); Chiral analysis: 100% ee; retention
time 9.85 min; column (R,R)Whelk O1, 250×4.6mm I.D., 5µ; mobile phase 50% ethanol (0.05%
DEA) in CO2; wavelength 220 nm. A crystalline sample of 23a was obtained by dissolving the
lyophilized powder in hot isopropanol in a 1 dram vial, then letting the vial stand in a capped
TLC chamber containing a layer of hexanes in the bottom, which allowed slow diffusion of hexanes into isopropanol. After two days, crystals (square plates) were collected. A smallmolecule X-Ray crystal structure of 23a showed it to have absolute (R) stereochemistry.
Crystallographic data are available in the Supporting Information.

syn

Pfizer Inc.

United States, US20150361067

REF

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• High-Throughput Screening to Identify Inhibitors of the Type I Interferon–Major Histocompatibility Complex Class I Pathway in Skeletal MusclePublication Name: ACS Chemical BiologyPublication Date: 2020-05-27PMCID: PMC7859889PMID: 32459468DOI: 10.1021/acschembio.0c00343
• Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Epigenetic Regulator Enhancer of Zeste Homolog 2Publication Name: The Journal of Pharmacology and Experimental TherapeuticsPublication Date: 2020-05PMID: 32094296DOI: 10.1124/jpet.119.263491
• Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)Publication Name: Journal of Medicinal ChemistryPublication Date: 2017-12-27PMID: 29211475DOI: 10.1021/acs.jmedchem.7b01375
• Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylationPublication Name: BloodPublication Date: 2011-02-24PMCID: PMC3062411PMID: 21190999DOI: 10.1182/blood-2010-11-321208

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Mechanism of action

Mevrometostat is a small molecule inhibitor that targets EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2).^[1][3] EZH2 plays a crucial role in epigenetic regulation by modifying gene expression patterns that control cellular fate decisions, including differentiation and self-renewal.^[1]

In prostate cancer, EZH2 dysregulation contributes to treatment resistance through multiple pathways, including:

• Silencing of tumor suppressor genes
• Activation of androgen receptor transcription factors
• Promotion of neuroendocrine transdifferentiation^[4]

Mevrometostat demonstrates dose-dependent EZH2 inhibition, leading to reactivation of tumor suppressor genes while suppressing genes involved in tumor progression.^[5]

Clinical development

Phase I/II trials

The primary clinical evaluation of mevrometostat is being conducted through a phase 1/2 dose-expansion study (NCT03460977) investigating the combination of mevrometostat with enzalutamide and androgen deprivation therapy in patients with mCRPC.^[6]

The dose-expansion portion of this study enrolled patients with mCRPC who had previously received abiraterone, with evidence of disease progression per modified Prostate Cancer Working Group 3 criteria.^[2]

Key efficacy results

In the randomized dose-expansion study, the combination of mevrometostat (1,250 mg twice daily on an empty stomach) plus enzalutamide demonstrated:

• 49% relative reduction in the rate of progression or death
• Approximately 8-month improvement in median radiographic progression-free survival (rPFS)
• Hazard ratio of 0.51 (90% CI: 0.28–0.95)^[7]

The median radiographic progression-free survival was 14.3 months with the combination therapy compared to 6.2 months with enzalutamide alone.^[8]

Phase III trials

Based on promising phase I/II results, Pfizer has initiated multiple phase 3 clinical trials:

MEVPRO-1 study

The MEVPRO-1 study (NCT06551324) is a randomized phase 3 trial evaluating mevrometostat in combination with enzalutamide versus physician's choice of therapy in patients with mCRPC previously treated with abiraterone acetate.^[9][10]

• Study design: Randomized 1:1 to receive mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg daily) versus physician's choice of enzalutamide or docetaxel
• Target enrollment: Approximately 600 patients
• Primary endpoint: Blinded independent central review-assessed rPFS per RECIST 1.1 and PCWG3 criteria
• Key secondary endpoint: Overall survival

MEVPRO-2 study

The MEVPRO-2 study (NCT06629779) is evaluating mevrometostat plus enzalutamide in androgen receptor pathway inhibitor (ARPI)-naïve patients with mCRPC.^[11][12]

Additional development

Pfizer has also initiated phase 3 trials evaluating mevrometostat plus enzalutamide in first-line metastatic castration-sensitive prostate cancer.^[8][13]

Safety profile

The most common adverse events considered related to mevrometostat treatment include:

• Diarrhea
• Dysgeusia (taste alteration)
• Anemia^[14]

Dose optimization studies found that mevrometostat 875 mg twice daily with food showed similar efficacy and better safety compared to the 1,250 mg dose on an empty stomach.^[15]

Pharmacokinetics

Based on safety and pharmacokinetic findings from phase 1 trials, mevrometostat 875 mg twice daily with food was selected as the recommended dose for phase 3 clinical development in combination with enzalutamide.^[16]

Regulatory status

As of 2025, mevrometostat remains an investigational agent under clinical development by Pfizer. The drug has not received regulatory approval from the Food and Drug Administration (FDA), European Medicines Agency (EMA), or other regulatory authorities.

See also

• Polycomb repressive complex 2
• Tazemetostat (approved EZH2 inhibitor)
• Prostate cancer
• Enzalutamide

References

1.  "Mevrometostat (PF-06821497)". Pfizer Oncology Development. Retrieved 11 September 2025.
2.  Schweizer MT, Calvo M, Moreno V, Mellado B, Castellano D, Spira AI, et al. (2025). "Mevrometostat (PF-06821497), an enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC): A randomized dose-expansion study". Journal of Clinical Oncology. 43 (5_suppl) LBA138. doi:10.1200/JCO.2025.43.5_suppl.LBA138.
3.  Schweizer MT, Penkov K, Choudhury AD, Calvo E, Frank RC, Liu L, et al. (2024). "Phase 1 trial of mevrometostat (PF-06821497), a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in castration-resistant prostate cancer (CRPC)". Journal of Clinical Oncology. 42 (16_suppl): 5061. doi:10.1200/JCO.2024.42.16_suppl.5061.
4.  "SUO 2024: Mevrometostat (PF-06821497) in Combination with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer Previously Treated with Abiraterone Acetate". UroToday. Retrieved 11 September 2025.
5.  "Mevrometostat and enzalutamide in mCRPC: gene expression and EZH2 modulation". VJ Oncology. 17 February 2025. Retrieved 11 September 2025.
6.  Pfizer (4 September 2025). A PHASE I DOSE ESCALATION AND EXPANDED COHORT STUDY OF PF 06821497 (MEVROMETOSTAT) IN THE TREATMENT OF ADULT PATIENTS WITH RELAPSED/REFRACTORY SMALL CELL LUNG CANCER (SCLC), CASTRATION RESISTANT PROSTATE CANCER (CRPC) AND FOLLICULAR LYMPHOMA (FL) (Report). clinicaltrials.gov.
7.  "ASCO GU 2025: Mevrometostat (PF-06821497), an EZH2 Inhibitor, in Combination with Enzalutamide in Patients with mCRPC". UroToday. Retrieved 11 September 2025.
8.  "Mevrometostat/enzalutamide combo shows rPFS benefit in mCRPC". Urology Times. 21 February 2025. Retrieved 11 September 2025.
9.  Agarwal N, Schweizer MT, Castro E, Azad A, George DJ, Chakrabarti J, et al. (2025). "Mevrometostat (PF-06821497) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate: The phase 3, randomized MEVPRO-1 study". Journal of Clinical Oncology. 43 (5_suppl) TPS288. doi:10.1200/JCO.2025.43.5_suppl.TPS288.
10.  Pfizer (4 September 2025). A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF PF-06821497 (MEVROMETOSTAT) IN COMBINATION WITH ENZALUTAMIDE COMPARED WITH ENZALUTAMIDE OR DOCETAXEL IN PARTICIPANTS WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER PREVIOUSLY TREATED WITH ABIRATERONE ACETATE (MEVPRO-1) (Report). clinicaltrials.gov.
11.  "ASCO GU 2025: Mevrometostat (PF-06821497) in Combination With Enzalutamide for ARPI-Naïve Patients With mCRPC: The Phase 3, Randomized MEVPRO-2 Trial". UroToday. Retrieved 11 September 2025.
12.  Pfizer (4 September 2025). A PHASE 3, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED STUDY OF PF-06821497 (MEVROMETOSTAT) WITH ENZALUTAMIDE IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MEVPRO-2) (Report). clinicaltrials.gov.
13.  Pfizer (4 September 2025). A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Mevrometostat (PF-06821497) With Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer (MEVPRO-3) (Report). clinicaltrials.gov.
14.  "ASCO 2025: Mevrometostat in Combination with Enzalutamide in Patients with mCRPC Previously Treated with Abiraterone Acetate". UroToday. Retrieved 11 September 2025.
15.  "Mevrometostat Plus Enzalutamide Improves rPFS vs Enzalutamide in Metastatic CRPC". OncLive. 21 February 2025. Retrieved 11 September 2025.
16.  "ASCO 2025: Safety and Pharmacokinetics of Mevrometostat in Combination with Enzalutamide in Patients with mCRPC". UroToday. Retrieved 11 September 2025.

Clinical data
Other names	PF-06821497
Identifiers
IUPAC name
CAS Number	1844849-10-0
PubChem CID	118572065
IUPHAR/BPS	10516
DrugBank	DB14799
ChemSpider	65321668
UNII	S4L4MM20B6
KEGG	D12845
ChEMBL	ChEMBL4080228
PDB ligand	CJD (PDBe, RCSB PDB)
Chemical and physical data
Formula	C22H24Cl2N2O5
Molar mass	467.34 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

/////////mevrometostat, enhancer of zeste homolog 2 (EZH2) inhibitor, antineoplastic, PF-06821497, PF 06821497, S4L4MM20B6

#mevrometostat, #enhancer of zeste homolog 2 (EZH2) inhibitor, #antineoplastic, #PF-06821497, #PF 06821497, #S4L4MM20B6

Mobinitinib

 

Mobinitinib

CAS1402709-93-6

MF C22H23Cl2N7 MW456.37

6-chloro-7-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-2-(1,3-dimethyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

6-chloro-7-{4-[(4-chlorophenyl)methyl]piperazin-1-yl}-2-(1,3-dimethyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine
dual FMS-like tyrosine kinase-3 (FLT3)-Aurora kinase inhibitor, antineoplastic, CCT241736, CCT 241736, ZE94SP78UG, EP0042, EP 0042

Mobinitinib (CCT241736) is an investigational, orally bioavailable, small-molecule, dual inhibitor targeting Aurora kinase and FLT3 (including ITD and D835Y mutations). It shows potent antineoplastic activity in preclinical models, including acute myeloid leukemia (AML), by inhibiting tumor cell proliferation and disrupting mitotic spindle assembly. It is a distinct compound from similarly named drugs like Momelotinib or Binimetinib. 

Key Details About Mobinitinib (CCT241736)

• Mechanism of Action: Acts as a dual inhibitor of Aurora kinases (A and B) and FMS-related tyrosine kinase 3 (FLT3). By inhibiting these kinases, it interferes with mitotic spindle assembly and chromosome segregation, leading to cell cycle arrest.
• Target Indications: Primarily studied for its potential to treat hematological malignancies and solid tumors that overexpress FLT3 or Aurora kinases. Preclinical studies show effectiveness in FLT3-ITD positive AML cell lines (e.g., MOLM-13, MV4-11).
• Preclinical Activity: Demonstrates strong anti-proliferative activity with $$ values in the sub-micromolar range (e.g., 0.1–0.3 $$M) in certain human tumor cell lines. It has shown significant tumor growth inhibition in mouse xenograft models at doses of 50-100 mg/kg.
• Chemical Properties: It is a 1H-imidazo[5-b]pyridine derivative. 

It is important to distinguish mobinitinib (CCT241736) from momelotinib, a JAK1/JAK2 inhibitor approved for myelofibrosis, and binimetinib, a MEK inhibitor for melanoma. 

Mobinitinib is an orally bioavailable inhibitor of both the serine/threonine protein kinase Aurora kinase and FMS-related tyrosine kinase 3 (FLT3; STK1; CD135; FLK2), with potential antineoplastic activity. Upon oral administration, mobinitinib specifically binds to and inhibits Aurora kinase and FLT3, which interferes with the activation of Aurora kinase- and FLT3-mediated signal transduction pathways. This may result in the disruption of the assembly of the mitotic spindle apparatus, the disruption of chromosome segregation and the inhibition of cell proliferation in tumor cells that overexpress Aurora kinase and/or FLT3. Aurora kinase plays essential roles in mitotic checkpoint control during mitosis. Aurora kinase and FLT3 are overexpressed in a variety of cancers and play key roles in tumor cell proliferation.

MOBINITINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Study to Evaluate the Safety and Tolerability of EP0042

CTID: NCT04581512

Phase: Phase 1/Phase 2

Status: Recruiting

Date: 2025-10-14

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013190319&_cid=P12-MLIU87-35242-1

5-Chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine

[00119] To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.152 g, 0.73 mmol) and isopropanol (22 mL) was added 1 -(4-chlorobenzyl)piperazine (0.165 g, 0.78 mmol) followed by diisopropylethylamine (0.17 mL, 0.97 mmol). The reaction mixture was heated at 45 °C for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (5 mL). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.215 g, 77%); ¹H-NMR (500 MHz, DMSO-d₆) 2.48 (br s, obscured by DMSO peak, 4H, piperazine C-H), 3.06 (br t, J = 4.3 Hz, 4H, piperazine C-H), 3.52 (s, 2H, NCH₂C₆H₄Cl), 6.95 (s, 2H, NH₂), 7.35 (d, J = 8.5 Hz, 2H) and 7.38 (d, J = 8.5 Hz, 2H) (3,5-ArH and 2,6- ArH), 8.06 (s, 1 H, 6-H); LC - MS (ESI, m/z): Rt = 1 .70 min - 382, 384, 386 [(M+H)⁺, Cl₂ isotopic pattern].

6-Chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

[00120] To a mixture of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1 -yl)-3-nitropyridin-2-amine (0.076 g, 0.20 mmol) and EtOH (4.0 ml.) was added 1 ,3-dimethyl-1 H-pyrazole-4-carbaldehyde (0.027 g, 0.22 mmol) followed by a freshly prepared aqueous solution of Na₂S₂O₄ (1 M; 0.85 mL, 0.85 mmol). The reaction mixture was stirred at 80 °C for 24 h, it was then allowed to cool to room temperature, concentrated in vacuo, and the residue was absorbed on silica gel and placed on a 10 g isolute silica column. Elution with ethyl acetate / dichloromethane (v/v; 1 :1 ), and then 4% methanol in ethyl acetate / dichloromethane (v/v; 1 :1 ) afforded the title compound as a white solid after trituration with diethyl ether (0.023 g, 25%).

[00121 ] ¹ H-NMR (500 MHz, DMSO-d₆) 2.51 (s, obscured by solvent peak, pyrazole 3-CH₃), 2.57 (br s, 4H, piperazine C-H), 3.54 (s, 2H, N-CH₂C₆H₄Cl), 3.68 (br s, 4H, piperazine C-H), 3.84 (s, 3H, pyrazole N-Me), 7.37 (d, J = 8.5 Hz, 2H) and 7.40 (d, J = 8.5 Hz, 2H) (C₆H₄Cl), 8.02 (s, 1 H), and 8.18 (s, 1 H) (pyrazole 5-H, and imidazo[4,5-b]pyridine 5-H), 12.95 (br s, 1 H, imidazo[4,5-b]pyridine N-H); LC - MS (ESI, m/z): Rt = 1.97 min - 456, 458, 460 [(M+H)⁺, Cl₂ isotopic pattern].

[00122] HRMS: Found: 456.1457, calculated for C₂₂H₂₄Cl₂N₇ (M+H)⁺: 456.1465.

LIT

• FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming ResistancePublication Name: Journal of Medicinal ChemistryPublication Date: 2021-03-10PMID: 33719439DOI: 10.1021/acs.jmedchem.0c01851
• Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736Publication Name: Blood AdvancesPublication Date: 2020-04-13PMCID: PMC7160287PMID: 32282883DOI: 10.1182/bloodadvances.2019000986
• Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology speciesPublication Name: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical SciencesPublication Date: 2019-11-01PMCID: PMC6892276PMID: 30953752DOI: 10.1016/j.ejps.2019.04.004
• Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid LeukemiaPublication Name: Journal of Medicinal ChemistryPublication Date: 2012-10-08PMCID: PMC3483018PMID: 23043539DOI: 10.1021/jm300952s

PAT

• Pharmaceutically active compoundsPublication Number: WO-2013190319-A1Priority Date: 2012-06-21
• Compound and, pharmaceutical compositionPublication Number: BR-112014032142-B1Priority Date: 2012-06-21
• Pharmaceutically active compoundsPublication Number: US-9447092-B2Priority Date: 2012-06-21Grant Date: 2016-09-20
• Pharmaceutically active compoundsPublication Number: CA-2876357-A1Priority Date: 2012-06-21
• Pharmaceutically active compoundsPublication Number: US-2015266868-A1Priority Date: 2012-06-21
• PHARMACEUTALLY ACTIVE COMPOUNDSPublication Number: RU-2015101702-APriority Date: 2012-06-21
• Pharmaceutically active compoundsPublication Number: SI-2864328-T1Priority Date: 2012-06-21

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////////////////mobinitinib, antineoplastic, CCT241736, CCT 241736, ZE94SP78UG, EP0042, EP 0042

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Mocaciclib

 

Mocaciclib

CAS 2766124-39-2

MF C33H36FN9O2 MW609.71

• 2-fluoro-N-[1-[2-[[[2-[[(3R,4R)-3-hydroxypiperidin-4-yl]methylamino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]isoquinolin-6-yl]prop-2-enamide
• 2-Fluoro-N-[1-[2-[[[2-[[[(3R,4R)-3-hydroxy-4-piperidinyl]methyl]amino]-8-(1-methylethyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl]amino]methyl]phenyl]-6-isoquinolinyl]-2-propenamide
• 2-fluoro-N-[1-[2-[[[2-[[(3R,4R)-3-hydroxypiperidin-4-yl]methylamino]-8-propan-2-ylpyrazolo[1,5-a][1,3,5]triazin-4-yl]amino]methyl]phenyl]isoquinolin-6-yl]prop-2-enamide

cyclin-dependent kinase (CDK) inhibitor, antineoplastic, Q 901,  CDK7-IN-21,

• OriginatorThe Lead Discovery Center; The Max Planck Institute of Biochemistry
• DeveloperQurient Co
• ClassAntineoplastics; Small molecules
• Mechanism of ActionCyclin-dependent kinase-activating kinase inhibitors
• Phase I/IISolid tumours
• 31 May 2024Preliminary efficacy, pharmacodynamics, pharmacokinetics and adverse events data from a phase I/II trial in Solid tumours presented at the 60th Annual Meeting of the American Society of Clinical Oncology (ASCO-2024)
• 21 May 2024Qurient Therapeutics enters into an Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI) for phase I/II trial in Small cell lung cancer (SCLC) and Solid tumours
• 21 May 2024Qurient Therapeutics plans phase I/II trial in Small cell lung cancer (SCLC) and Solid tumours

Mocaciclib (Q-901) is an orally bioavailable, selective cyclin-dependent kinase (CDK) inhibitor with potent activity against CDK2, CDK4, and CDK6. Preclinical data show that Mocaciclib inhibits CDK2/cyclin E with an IC₅₀ of 1.1 nM, CDK4/cyclin D1 with an IC₅₀ of 2.5 nM, and CDK6/cyclin D3 with an IC₅₀ of 4.1 nM, demonstrating high potency in enzymatic assays. In cancer cell lines, Mocaciclib suppresses retinoblastoma protein (Rb) phosphorylation, leading to G1 cell cycle arrest and growth inhibition in Rb-positive tumor models. It has shown antiproliferative effects in various preclinical models, including breast and lung cancers.

Mocaciclib is a selective inhibitor of cyclin-dependent kinase 7 (CDK7), with potential antineoplastic activity. Upon administration, mocaciclib selectively targets, covalently binds to and inhibits the activity of CDK7, thereby inhibiting CDK7-mediated signaling. The inhibition of CDK7 prevents phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II, thereby preventing transcription of important cancer-promoting genes. It prevents phosphorylation of the cell cycle kinases CDK1, 2, 4, and 6, thereby disrupting uncontrolled cell cycle progression. Altogether, this may induce apoptosis, cause cell cycle arrest, inhibit DNA damage repair and inhibit tumor cell proliferation in certain cancers that are dependent on CDK7-mediated transcriptional regulation and signaling. CDK7, a serine/threonine kinase, plays a role in controlling cell cycle progression and transcriptional regulation, and promotes the expression of key oncogenes through the phosphorylation of RNA polymerase II. It is overexpressed in multiple cancers.

SYN

[WO2019197546A1]

compound 64

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019197546&_cid=P20-MLKA3Y-79608-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022117504&_cid=P20-MLK9ZO-76153-1

This is compound 64, as disclosed in WO2O19/197546. 

PAT

• Compounds having cyclin-dependent kinase(cdk)-inhibitory functionPublication Number: WO-2022117504-A1Priority Date: 2020-12-02
• Substituted pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines as CDK inhibitorsPublication Number: US-11858937-B2Priority Date: 2018-04-11Grant Date: 2024-01-02
• Pharmaceutically active pyrazolo-triazine and/or pyrazolo-pyrimidine derivativesPublication Number: US-2021139483-A1Priority Date: 2018-04-11

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//////////mocaciclib, cyclin-dependent kinase (CDK) inhibitor, antineoplastic, Q 901,  CDK7-IN-21,

#mocaciclib, #cyclin-dependent kinase (CDK) inhibitor, #antineoplastic, #Q 901, #CDK7-IN-21,

Mosperafenib

 

Mosperafenib

CAS 2649372-20-1

MF C20H17F2N5O4S MW 461.4 g/mol

• (3R)-N-{2-cyano-4-fluoro-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-fluoropyrrolidine-1-sulfonamide
• (3R)-N-(2-cyano-4-fluoro-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide

(3R)-N-{2-cyano-4-fluoro-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]phenyl}-3-fluoropyrrolidine-1-sulfonamide
B-Raf (BRAF) inhibitor, antineoplastic, RG6344, RO7276389, RG 6344, RO 7276389, 881-730-4, B-Raf IN 2

Mosperafenib is a small molecule drug. The usage of the INN stem '-rafenib' in the name indicates that Mosperafenib is a Raf (rapidly accelerated fibrosarcoma) kinase inhibitor. Mosperafenib has a monoisotopic molecular weight of 461.1 Da.

Mosperafenib (RG6344, RO7276389) is an investigational, oral, "paradox-breaker" BRAF inhibitor developed by Roche for treating BRAF-mutated cancers, particularly BRAF V600E-mutant metastatic colorectal cancer. It acts as a potent, selective inhibitor that avoids MAPK pathway overactivation in non-V600E contexts, showing superior preclinical activity and brain penetration compared to existing inhibitors like encorafenib. 

Key Aspects of Mosperafenib:

• Mechanism: As a "paradox-breaker" BRAF inhibitor, it avoids the paradoxical MAPK pathway activation seen with earlier inhibitors. It inhibits BRAF mutants ($$) and is effective in RAF dimer-mediated resistant models.
• Clinical Development: Currently in Phase I clinical trials for BRAF V600E-mutant colorectal cancer.
• Preclinical Performance: In studies, it demonstrated higher antitumor activity than encorafenib/cetuximab combinations, even in BRAFi-naïve models.
• Combination Potential: It is being evaluated in combination with cetuximab and FOLFOX.
• Targeting: It targets BRAF V600E/K/A/D mutations. 

• OriginatorRoche
• ClassAntineoplastics; Fluorinated hydrocarbons; Fluorobenzenes; Nitriles; Phenyl ethers; Pyridones; Pyrrolidines
• Mechanism of ActionProto-oncogene protein b-raf inhibitors
• Phase IMalignant melanoma; Solid tumours
• 18 Sep 2025Chemical structure information added.
• 30 May 2025Efficacy, pharmacokinetics and adverse events data from a phase I trial in Solid tumors presented at the 61st Annual Meeting of the American Society of Clinical Oncology (ASCO-2025)
• 25 Apr 2025Efficacy, pharmacokinetics and adverse events data from a phase I trial in Solid tumors presented at the 116th Annual Meeting of the American Association for Cancer Research (AACR-2025)

SYN

[WO2021116050]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021116050&_cid=P11-MLLPKF-91057-1

SYN

US20240174621,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US430558420&_cid=P11-MLLPRY-96230-1

3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (Example 1)

R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, Eq: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, Eq: 2.2) were suspended in dry DMF (10.2 ml) under an argon atmosphere. The reaction was stirred at 50° C. for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (1.12 g, 3.58 mmol, Eq: 1.0) in DMF (25.5 ml) was added. The reaction mixture was stirred at 100° C. for 15 h, then concentrated in vacuo. The residue was taken up in sat. aq. NH ₄Cl (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous layer was extracted further with 2×100 mL EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na ₂SO ₄), filtered and concentrated in vacuo. The water layer was back-extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na ₂SO ₄), filtered and concentrated in vacuo. The residue was diluted with DCM and MeOH, and concentrated onto silica. Purification by flash chromatography (120 g, 0.5-2% MeOH/DCM) gave an off-white solid which was triturated with 1:1 heptane/DCM (20 mL) with sonication, then dried in vacuo to give the title compound as a colourless solid (1.087 g, 66% yield). MS (ESI) m/z: 426.2 [M+H] ⁺. Chiral SFC: RT=4.594 min [Chiralpak IC column, 4.6×250 mm, 5 μm particle size (Daicel); gradient of 20-40% MeOH containing 0.2% NHEt ₂ over 8 min; flow: 2.5 mL/min; 140 bar backpressure].

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021116055&_cid=P11-MLLPB3-84537-1

Refences compounds AR-25, AR-30 and AR-31 were prepared according to the synthesis disclosed in WO2012/118492 in example 25, example 30 and example 31 respectively.

6-hydroxy-3-methyl-quinazolin-4-one

2-Amino-5-hydroxybenzoic acid (10 g, 65.3 mmol, Eq: 1.0) and A-methylformamide (30 g, 29.9 mL, 503 mmol, Eq: 7.7) were heated at 145 °C for 21 h 45 min, then cooled to rt. The reaction mixture was diluted with 50 mL H₂O and stirred at rt for 20 min. The resulting precipitate was collected by filtration. The light brown solid was washed 3 × with 20 mL water. The solid was taken up in toluene and evaporated to dryness (3 ×). The solid was dried in vacuo at 40 °C overnight under high vacuum to give the title compound as a light brown solid (10.3 g, 89% yield). MS (ESI) mlz: 177.1 [M+H]⁺.

3.6-difluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile

Cesium carbonate (3.22 g, 9.79 mmol, Eq: 1.15) was added at rt to a solution of 6-hydroxy-3-methylquinazolin-4-one (1500 mg, 8.51 mmol, Eq: 1.0) in N,N-dimethylformamide (35 mL). The mixture was stirred for 30 min at rt then 2,3,6-trifluorobenzonitrile (1.47 g, 1.08 ml, 9.37 mmol, Eq: 1.1) was added. After 1 h, the reaction was cooled on ice and diluted with water (120 mL). The resultant solid was collected by filtration, washed with iced water (100 mL) and heptane (100 mL) and suction-dried. The solid was taken up in toluene and evaporated to dryness (3 ×) then dried overnight in vacuo to give the title compound as a light brown solid (2.58 g, 97% yield). MS (ESI) m/z: 314.1 [M+H]+.

(3R)-3 -fluoropyrrolidine- 1 -sulfonamide

(R)-3 -Fluoropyrrolidine hydrochloride (1.8 g, 14.3 mmol, Eq: 1.2) was added to a solution of sulfuric diamide (1.148 g, 11.9 mmol, Eq: 1.0) and triethylamine (2.42 g, 3.33 mL, 23.9 mmol, Eq: 2) in dioxane (10 mL). The reaction was stirred in a sealed tube at 115 °C for 15.5 h then cooled to rt and concentrated in vacuo. The residue was diluted with DCM, evaporated with silica gel to dryness and transferred to a column. Purification by flash chromatography (40 g silica, 80% EtOAc) gave the title compound as a white crystalline solid (1.82 g, 91% yield). MS (ESI) m/z: 169.1 [M+H]⁺.

(3S)-3 -fluoropyrrolidine- 1 -sulfonamide

Triethylamine (304 mg, 419 μl, 3.01 mmol, Eq: 2.0) was added to a suspension of sulfuric diamide (146 mg, 1.5 mmol, Eq: 1.0) and (S)-3 -fluoropyrrolidine hydrochloride (234 mg, 1.8 mmol, Eq: 1.2) in dioxane (1.3 ml). The reaction was stirred in a sealed tube at 115°C for 16 h 35 min, then concentrated in vacuo. The residue was diluted with MeOH and evaporated with silica gel to dryness and transferred to a column. Purification by flash chromatography (40 g silica, 0-8% MeOH/DCM) gave the title compound as a light yellow solid (193 mg, 75% yield). MS (ESI) m/z: 169.1 [M+H]⁺.

(3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1 -sulfonamide (Example 1)

(R)-3-Fluoropyrrolidine-1-sulfonamide (1.26 g, 7.51 mmol, Eq: 2.1) and cesium carbonate (2.56 g, 7.87 mmol, Eq: 2.2) were suspended in dry DMF (10.2 ml) under an argon atmosphere. The reaction was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (1.12 g, 3.58 mmol, Eq: 1.0) in DMF (25.5 ml) was added. The reaction mixture was stirred at 100 °C for 15 h, then concentrated in vacuo. The residue was taken up in sat. aq. NH₄Cl (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous layer was extracted further with 2 x 100 mL EtOAc. The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The water layer was back-extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was diluted with DCM and MeOH, and concentrated onto silica. Purification by flash chromatography (120 g, 0.5-2% MeOH/DCM) gave an off-white solid which was triturated with 1 : 1 heptane/DCM (20 mL) with sonication, then dried in vacuo to give the title compound as a colourless solid (1.087 g, 66% yield). MS (ESI) mlz: 426.2 [M+H]⁺. Chiral SFC: RT = 4.594 min [Chiralpak IC column, 4.6 x 250 mm, 5μm particle size (Daicel); gradient of 20 - 40% MeOH containing 0.2% NHEt₂ over 8 min; flow: 2.5 mL/min; 140 bar backpressure],

(3S)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1 -sulfonamide (Example 2)

(S)-3-Fluoropyrrolidine-1-sulfonamide (181 mg, 1.08 mmol, Eq: 2.1) was dissolved in DMF (1.6 ml). At rt cesium carbonate (368 mg, 1.13 mmol, Eq: 2.2) was added and the reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and a solution of 3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile (160.8 mg, 513 μmol, Eq: 1.0) in DMF (4 ml) was added. The reaction mixture was stirred at 105 °C for 2 h 50 min then concentrated in vacuo. The residue was taken up in DCM and washed with sat. aq. NH₄Cl. The aq. layer was back-extracted twice with DCM. The combined organic layers were dried over Na₂SO₄, filtrated and evaporated. The residue (brown oil) was diluted with DCM and transferred to a column. Purification by flash chromatography (80 g, 0-100% EtOAc in DCM) gave a solid which was further purified by SFC to give the title compound as a light yellow solid (119 mg, 50% yield). MS (ESI) m/z: 426.2 [M+H]⁺. Chiral SFC: RT = 4.411 min [Chiralpak IC column, 4.6 x 250 mm, 5μm particle size (Daicel); gradient of 20 - 40% MeOH containing 0.2% NHEt₂ over 8 min; flow: 2.5 mL/min; 140 bar backpressure].

PAT

New methylquinazolinone derivatives

Publication Number: AU-2020403443-A1

Priority Date: 2019-12-10

• Methylquinazolinone derivativesPublication Number: US-2024174621-A1Priority Date: 2019-12-10
• New methylquinazolinone derivativesPublication Number: EP-4073065-B1Priority Date: 2019-12-10Grant Date: 2025-02-19
• Methylquinazolinone derivativesPublication Number: US-2022298119-A1Priority Date: 2019-12-10
• Novel BRAF inhibitors as anomalous breakersPublication Number: CN-114746405-BPriority Date: 2019-12-10Grant Date: 2024-03-26
• New BRAF inhibitors as paradox breakersPublication Number: AU-2020403082-A1Priority Date: 2019-12-10

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