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peroxisome proliferator-activated receptor alpha (PPARĪ±) antagonist, antineoplastic, TPST 1120, FDA Fast Track, Orphan Drug, 1EQ4LQN9N3
Amezalpat (formerly TPST-1120) is an investigational, oral, small-molecule inhibitor targeting peroxisome proliferator-activated receptor alpha (PPAR being developed by Tempest Therapeutics. It works by directly targeting tumor cells and reducing immune suppression in the tumor microenvironment. In combination with atezolizumab and bevacizumab, it has shown improved survival in hepatocellular carcinoma (HCC) patients, receiving FDA Fast Track and Orphan Drug designations.
Key Details on Amezalpat
Indication: Primarily being studied for unresectable or metastatic hepatocellular carcinoma (liver cancer).
Mechanism: A selective, competitive antagonist of PPAR, which plays a role in fatty acid metabolism in cancer cells.
Clinical Efficacy: A phase 1b/2 study indicated that adding amezalpat to standard-of-care (atezolizumab + bevacizumab) improved median overall survival to 21 months compared to 15 months for the control, according to Tempest Therapeutics.
Trial Status: A pivotal Phase 3 study (NCT06680258) to evaluate this combination as a first-line treatment is planned for 2025.
Other Potential Uses: Preclinical data suggests potential activity in other advanced solid tumors, including renal cell carcinoma.
Disclaimer: Amezalpat is an investigational agent and is not yet approved by the FDA for widespread clinical use.
Amezalpat is an orally bioavailable, small molecule, selective and competitive antagonist of peroxisome proliferator activated receptor alpha (PPARa), with potential immunomodulating and antineoplastic activities. Upon oral administration, amezalpat targets, binds to and blocks the activity of PPARa, thereby blocking transcription of PPARa target genes leading to an intracellular metabolism shift from fatty acid oxidation (FAO) to glycolysis in FAO-dependent tumors and reducing the production of fatty acids in the tumor microenvironment (TME). As fatty acids are essential for tumor cell growth in FAO-dependent tumor cells and are needed for the metabolism of suppressive immune cells in the TME, including regulatory T-cells (Tregs), reducing the amount of fatty acids leads to a direct killing of FAO-dependent tumor cells. It also skews macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype and facilitates the cytotoxicity of immune effector cells, thereby stimulating an anti-tumor immune response and further killing tumor cells. Amezalpat also restores the natural inhibitor of angiogenesis thrombospondin-1 (TSP-1) and stimulator of interferon genes (STING) in the TME. PPARa, a ligand-activated nuclear transcription factor and metabolic checkpoint, regulates the expression of FAO genes and lipid metabolism. It plays a key role in immunosuppression in the TME. FAO is a metabolic pathway essential to tumor growth, survival and immunosuppression.
2-(3'-(3-(l-(4-(tertbutyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,T-biphenyl]-3-yl)acetic acid, depicted below as Compound A
Amsulostat is an orally available, small-molecule, irreversible inhibitor of all lysyl oxidases (LOX) family members, with potential antifibrotic activity. Upon oral administration, amsulostat targets, binds to and inhibits the activity of all enzymes in the LOX family. This prevents the post-translational oxidative deamination of lysine residues on target proteins, including collagen and elastin, and reduces the formation of deaminated lysine (allysine), the formation of inter- and intramolecular cross-linkages and may prevent remodeling of the extracellular matrix (ECM), thereby reducing fibrotic tissue formation in certain chronic fibrotic diseases. LOX is often upregulated in fibrotic tissue and plays a key role in fibrosis.
Amsulostat (formerly PXS-5505) is an orally available, investigational, pan-lysyl oxidase (pan-LOX) inhibitor designed by Syntara to treat fibrotic diseases and solid tumors. It works by preventing collagen cross-linking and remodeling of the extracellular matrix, effectively reducing fibrosis. The drug is currently in Phase 2 clinical trials for myelofibrosis, showing promise in reducing symptom burden and spleen volume, and is also being studied for myelodysplastic syndrome (MDS) and pancreatic cancer.
Key Aspects of Amsulostat:
Mechanism of Action: Irreversibly inhibits all LOX family members (LOX, LOXL1-4), reducing fibrotic tissue.
Clinical Status (Myelofibrosis): Phase 2a data showed 73% of patients (who were suboptimal responders to ruxolitinib) achieved reduction in total symptom score, with significant spleen volume reduction.
Clinical Status (Other Cancers): Phase 2 trials (AZALOX) are evaluating its use in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). It is also being tested in combination with chemotherapy for pancreatic cancer to improve drug delivery to tumors.
Regulatory Status: Has received Orphan Drug Designation for primary myelofibrosis from the FDA (USA) and EMA (Europe).
Safety Profile: Clinical trials have reported it is well-tolerated with no treatment-related serious adverse events in early findings.
Amsulostat's ability to target the stiff, fibrotic environment surrounding tumors makes it a promising "add-on" therapy to increase the effectiveness of existing cancer treatments, including chemotherapy and immunotherapy.
An orally available, small-molecule, irreversible inhibitor of all lysyl oxidases (LOX) family members, with potential antifibrotic activity. Upon oral administration, amsulostat targets, binds to and inhibits the activity of all enzymes in the LOX family. This prevents the post-translational oxidative deamination of lysine residues on target proteins, including collagen and elastin, and reduces the formation of deaminated lysine (allysine), the formation of inter- and intramolecular cross-linkages and may prevent remodeling of the extracellular matrix (ECM), thereby reducing fibrotic tissue formation in certain chronic fibrotic diseases. LOX is often upregulated in fibrotic tissue and plays a key role in fibrosis.
Andamertinib (also known as PLB1004) is an investigational, orally bioavailable, and irreversible small-molecule inhibitor of the epidermal growth factor receptor (EGFR). It is primarily being developed to treat non-small cell lung cancer (NSCLC) with specific genetic mutations.
Key Clinical & Therapeutic Features
Target Mutations: It specifically targets EGFR exon 20 insertion (ex20ins) mutations, which are often resistant to standard first- and second-generation EGFR inhibitors.
Broad Selectivity: Beyond ex20ins, it also shows activity against classical mutations like Del19, L858R, and the resistance mutation T790M.
Brain Penetration: Andamertinib is designed to cross the blood-brain barrier, making it potentially effective for patients with brain metastases.
Clinical Performance: In phase 2 studies (e.g., the KANNON study), it demonstrated a confirmed objective response rate (ORR) of 42.7% and a median progression-free survival of 6.2 months in pretreated patients.
Regulatory Status (as of Early 2026)
China: A New Drug Application (NDA) was accepted by the National Medical Products Administration (NMPA) in May 2025 and granted priority review for treating NSCLC with EGFR ex20ins mutations.
Global: It remains in various stages of clinical trials globally, including studies for first-line treatment and combination therapies with other agents like vebreltinib.
Andamertinib is an orally bioavailable, mono-anilino-pyrimidine, mutant-selective epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Upon oral administration, andamertinib targets, binds to and irreversibly inhibits the activity of various EGFR mutations, including exon 20 insertion (Ex20ins) activating mutations, the gatekeeper mutation T790M, ExDel19, and L858R. This prevents EGFR-mediated signaling, induces cell death and inhibits tumor growth in tumor cells expressing these EGFR mutations. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization.
Anvumetostat (also known as AMG 193) is an orally available, small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), primarily being developed for the treatment of advanced solid tumours with MTAP-null (methylthioadenosine phosphorylase-deficient) mutations.
Mechanism of Action
Targeting PRMT5: It is a potent and selective MTA-cooperative inhibitor of PRMT5.
Synthetic Lethality: In cells where the MTAP gene is deleted (a common occurrence in various cancers), a metabolite called MTA (methylthioadenosine) accumulates. Anvumetostat selectively binds to the PRMT5-MTA complex, inhibiting its methyltransferase activity.
Cellular Impact: By blocking PRMT5, the drug reduces the methylation of arginine residues in histones (H2A, H3, and H4), which can lead to decreased growth or death of cancer cells.
Clinical Development
Anvumetostat was initially developed by Amgen, Inc. and is currently in clinical trials. Institute (.gov) +1
Current Status: As of early 2026, it is in Phase 2 of global research and development.
Study Focus: Trials are evaluating its efficacy both as a monotherapy and in combination with other treatments for adult patients with metastatic or locally advanced MTAP-null cancers.
Key Identifiers
Alternate Names: AMG 193, AMG-193.
Chemical Class: Orally bioavailable small molecule.
Genetic Biomarker: Specifically targets cancers with MTAP-null status
Anvumetostat is an orally available small molecule inhibitor of protein arginine methyltransferase 5 (PRMT5), with potential antiproliferative and antineoplastic activities. Upon oral administration, anvumetostat selectively binds to PRMT5 and inhibits its function. By inhibiting its methyltransferase activity, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cells, including cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival. Methylthioadenosine phosphorylase (MTAP) is deleted in certain cancer cells leading to an accumulation of methylthioadenosine (MTA). As MTA inhibits PRMT5, MTAP-null cancer cells are specifically sensitive to PRMT5 inhibitors.
[0163] Examples 481 and 482: (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone
[0164] Step 1: To a solution of 3-(4-(trifluoromethyl)phenyl)morpholine (0.100 g, 0.432 mmol, Enamine), 4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c][l,7]naphthyridine-8-carboxylic acid hydrochloride (138) (0.271 g, 0.649 mmol) and l,l'-dimethyltriethylamine (0.559 g, 0.755 mL, 4.32 mmol, Sigma- Aldrich Corporation) in DMF (4 mL) was added bromotripyrrolidinophosphonium hexafluorophosphate (0.202 g, 0.432 mmol, Sigma-Aldrich Corporation) and the resulting mixture was heated at 50 °C for 30 min. The reaction was brought to rt, diluted with water, sat.NaHCCh and extracted with EtOAc (3x). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was then chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-((2,4-dimethoxybenzyl)amino)- 1 ,3 -dihy drofuro [3 ,4-c] [ 1 ,7]naphthyridin-8-y 1) (3 - (4 -(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2% yield) as a light yellow solid, m/z (ESI): 595 (M+H)+.
[0165] To a solution of (4-((2,4-dimethoxybenzyl)amino)-l,3-dihydrofuro[3,4-c] [l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (0.160 g, 0.269 mmol, 62.2 % yield) in DCM (2 mL) was added TFA (14.80 g, 10 mL, 130 mmol, Aldrich) and the resulting mixture was heated at 50 °C for 1 h. The reaction was concentrated, washed with 10% Na2CO3 and extracted with DCM. The combined organics were concentrated and chromatographed on silica gel using 0-50% 3:1 EtOAc/EtOH in heptane to afford (4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone as the TFA salt (0.078 g, 0.140 mmol, 32.3% yield) as an off-white solid, m/z (ESI): 445 (M+H)+.
(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone 2,2,2-trifluoroacetate were separated via preparative SFC using a Chiral Technologies AD column (150 x 21 mm, 5mm) with a mobile phase of 60% Liquid CO2 and 40% MeOH with 0.2% TEA using a flowrate of 80 mL/min to generate peak 1, (S)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of >99%, and peak 2, (R)-(4-amino-l,3-dihydrofuro[3,4-c][l,7]naphthyridin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone with an ee of 99.28%. Peak assignment determined by
SFC with AD column with 60% Liquid CO2 and 40% MeOH with 0.2% TEA and absolute
Example 4. Synthesis of Compound I - (4-amino-1 ,3-di hydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone
Reaction Scale 1
[0137] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (1.0 kg, 4.3 mol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (1.2 kg, 5.2 mmol, 1.2- equiv), and DMF, (6.6 kg, 7.0 V) were charged to a clean, dry reactor. To the mixture was added triethylamine (1.1 Kg, 13.8 mol, 2.6 equiv). The mixture was cooled to 10 ± 5 °C and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (1.67 kg, 5.2 mol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (0.94 Kg, 1 V) was added. The reaction mixture was warmed to 25 ± 5 °C and stirred over 18 hours. Water (1 .0 kg, 1 V) was charged followed by MeCN (1 .6 kg, 2 V) and the reaction mass was warmed to 45 °C. Next, water (7.0 Kg, 7 V) was added over 30 min. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (10 g, 22 mmol, 0.01 equiv), was charged and the mixture was stirred at 45 °C for over 2 hours before being cooled to 20 °C over 10 hours. Water (12.0 kg, 12 V) was added over 2 hours at 20 °C and further stirred for over 4 hours before being filtered. The reactor was rinsed with a mixture of 10% DMF in water (9.83 kg, 10 V) and the resulting rinse mixture was used to wash the cake. The reactor was rinsed with a mixture of water (10.0k kg, 10 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated once more with water (10.0k kg, 10V). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-
[0138] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (85.0 g, 352.2 mmol, 1.0 equiv), (3S)-3-[4-(trifluoromethyl)phenyl]morpholine (99.6 g, 422.6 mmol, 1.2- equiv), and DMF, (674 mL, 8.7 mol, 7.9 V) were charged to a clean, dry 5 L reactor. To the mixture was added 1 -methylimidazole (75.2 g, 916.2 mmol, 2.6 equiv). The mixture was cooled to 0 °C and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (118.6 g, 422.6 mmol, 1.2 equiv) was added slowly. Next, an additional amount of DMF (170 mL, 2 V) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred overnight. Next, the reaction mass was warmed to 45 °C and 2-methyltetrahydrofuran, (169.2 mL, 2 V) was added followed by slow addition of water (850 mL, 10 V) over 30 min by addition funnel. A seed lot of 4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (1.6 g, 3.5 mmol, 0.1 equiv), was charged as a slurry in a 1 :1 v/v of DMF and water (31 .3 mL) and the mixture was stirred at 45 °C for approximately 12 hrs. Water (510 mL, 6 V) was added over 1 h 10 min by addition funnel and the mixture was further stirred at 45°C for 30 min before being filtered. The reactor was rinsed with water (340 mL, 4 V) and the resulting rinse mixture was used to wash the cake. This rinsing and washing protocol was repeated twice more. The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone. LCMS: 445.20 1H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, J=3.5 Hz, 2H), 4.44 (br d, J=12.3 Hz, 1 H), 4.08 (br d, J=13.4 Hz, 1 H), 3.96 (dd, J=12.3, 3.7 Hz, 1 H), 3.86 (br dd, J=11.4, 3.0 Hz, 1 H), 3.66 (td, J=11.4, 3.0 Hz, 1 H), 3.28 (m, 1 H).
Reaction Scale 3:
[0139] 4-Amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridine-8-carboxylic acid (Compound A') (20.0 g, 86.5 mmol, 1.0 equiv) was added to dimethylsulfoxide (400 mL) at 20 °C. To the mixture was added 1 ,T-carbonyldiimidazole (15.4 g, 95.2 mmol, 1.1 equiv) and the mixture was heated to 60 °C for 1 hour. A solution of (S)-3-(4-(trifluoromethyl)phenyl)morpholin-4-ium chloride (25.5 g, 95.2 mmol, 1.1 equiv) and dimethylsulfoxide (40 mL) was added, and the mixture was heated to 80 °C for 11 hours. The reaction mixture was cooled to 35 °C, then water (265 mL) was added, then the batch was cooled to 20 °C. The reaction was filtered, washed with 40% water:DMSO (80 mL), then washed with water (100 mL). The cake was dried under vacuum with a stream of nitrogen to afford (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (Compound I). LCMS: 445.20 1H NMR (400 MHz, DMSO-d6 at 130 °C): 8.87 (s, 1 H), 7.80 (s, 1 H), 7.73 (d, J=8.7 Hz, 2H), 7.71 (d, J=8.7 Hz, 2H), 6.58 (br s, 2H), 5.72 (br s, 1 H), 5.38 (m, 2H), 5.09 (t, >3.5 Hz, 2H), 4.44 (br d, >12.3 Hz, 1H), 4.08 (br d, >13.4 Hz, 1 H), 3.96 (dd, >12.3, 3.7 Hz, 1 H), 3.86 (br dd, >11 .4, 3.0 Hz, 1 H), 3.66 (td, >11 .4, 3.0 Hz, 1 H), 3.28 (m, 1 H).
Recrystallization of Compound I
[0140] A clean, dry 5 L reactor was charged with (4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl]methanone (279.7 g, 0.6 mol, 1.0 equiv) followed by acetone (6.2 L,
22 V). The mixture was stirred at 40 °C for 15 minutes before cooling to 25 °C. The reactor was discharged into a flask and the reactor was rinsed with acetone and the process stream was polish-filtered back into the reactor.
The reactor jacket was set to 65 °C and the reaction volume was reduced to approximately 6 V by distillation at atmospheric pressure, crystallization was observed. The reaction temperature was set to cool to 20 °C over two hours. Heptane (2.8 L, 10 V) was added over two hours. The slurry was filtered and the cake was washed twice with a 4:1 Heptane/acetone mix (750 mL, 3 V each) and dried under vacuum with a nitrogen purge to afford (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl)-[(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl] methanone.
, which plays a role in fatty acid metabolism in cancer cells.
reduction in total symptom score, with significant spleen volume reduction.
