Rigosertib

Rigosertib

(E)-2-(2-Methoxy-5-(2-(2′,4′,6′-trimethoxyphenyl)vinylsulfonamido)phenylamino)acetic Acid

THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. Glycine, N-[2-methoxy-5-[[[(1E)-2-(2,4,6-Trimethoxyphenyl)ethenyl]sulfonyl]
methyl]phenyl]-
2. N-[2-methoxy-5-({[(1E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonyl}methyl)
phenyl]glycine

MOLECULAR FORMULA C21H25NO8S
MOLECULAR WEIGHT 451.5

SPONSOR Onconova Therapeutics
CODE DESIGNATION --ON 01910
CAS REGISTRY NUMBER 592542-59-1

Chemical Formula: C21H24NNaO8S

Molecular Weight: 473.47

1225497-78-8

sodium (E)-2-((2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)phenyl)amino)acetate

US Patent No.7,598,232, such as in Schemes 1-10

M.V. Reddy et al. J. Med. Chem. 2011, 54, 6254

Rigosertib (ON-01910 sodium salt)  is a synthetic benzyl styryl sulfone analogue with potential antineoplastic activity. Polo-like kinase 1 inhibitor ON 01910.Na inhibits polo-like kinase1 (Plk1), inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the G1 and G2 stage without apoptosis in normal cells. This agent may exhibit synergistic antitumor activity in combination with other chemotherapeutic agents. Plk1, named after the polo gene of Drosophila melanogaster, is a serine/threonine protein kinase involved in regulating mitotic spindle function in a non-ATP competitive manner.

Rigosertib is an inhibitor of two important cellular signaling pathways, PI3K and PLK, both of which are frequently over-active in cancer cells. PI3K signaling promotes the growth and survival of cells under stressful conditions, such as under low oxygen levels that are often found in tumors. If the PI3K pathway is over-active, apoptosis of cancer cells is diminished, leading to excessive cellular growth. By inhibiting the PI3K pathway, rigosertib promotes tumor cell apoptosis. Rigosertib also influences signals along the PI3K pathway, such as those leading to the production of cyclin D1.

The PLK pathway plays a critical role in maintaining proper organization and sorting of chromosomes during cell division. Too much PLK activity in cancer cells results in uncontrolled proliferation. By modulating PLK pathway activity in cancer cells, rigosertib inhibits cellular division, leading to chromosome disorganization and death in these cells.

Due to this dual effect on tumor cell survival and division pathways, we believe that rigosertib has potential to treat a variety of cancer types, including hematological diseases and solid tumors.  Ongoing clinical trials are evaluating the activity of rigosertib in:

• Myelodysplastic Syndromes (MDS)
• Pancreatic Cancer
• Head & Neck Cancer
• Other hematological diseases and solid tumors

Ongoing and completed Phase 1, Phase 2 and Phase 3 clinical trials have generated data in over 850 patients with advanced, heavily pre-treated solid tumors and hematological diseases and have demonstrated a desirable safety profile for rigosertib.

Rigosertib is a substituted styryl benzylsulfone that inhibits multiple kinases including phosphatidylinositol 3-kinase (PI3-K) and polo-like kinase 1 (PLK-1). Phase 1 and 2 studies have demonstrated its ability to delay transition of myelodysplasia syndrome (MDS) to acute myologenous leukemia (AML), which is a serious disease associated with high mortality. As a result, it is being studied in a Phase 3 trial in MDS patients who have failed previous chemotherapy with accepted agents

Polo-like kinases are enzymes that are involved in cell division and checkpoint regulation of mitosis; they also help maintain DNA integrity. They are overexpressed in a variety of human tumours but not in normal cells, making them a potential target for cancer chemotherapy. Rigosertib, a small molecule agent designed to target these kinases, is being developed by US biotech company Onconova.It remains active against numerous cancer cells that are resistant to other drugs, without affecting normal cells. Trials are furthest advanced in myelo-dysplastic syndrome (MDS). In a Phase I/II trial, patients with the MDS or acute myeloid leukaemia were given the drug by continuous intravenous infusion over a period of 72 to 144 hours every two weeks, for between five and 70 weeks.Three achieved a marrow complete response and two a haematological improvement. The five non-responders were the five patients with AML. It was well tolerated.

US7598232

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NMR

J. Med. Chem., 2013, 56 (13), pp 5562–5586

DOI: 10.1021/jm400575x

(E)-2-(2-Methoxy-5-(2-(2′,4′,6′-trimethoxyphenyl)vinylsulfonamido)phenylamino)acetic Acid (25a)

 pale-yellow solid, mp 110–112 °C. ¹H NMR(DMSO-d₆, 300 MHz): δ 3.71 (s, 2H, CH₂), 3.82 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 3.87 (s, 6H, 2 × OCH₃), 6.26 (s, 2H, Ar–H), 6.48 (d, J = 1.8 Hz, 1H, Ar–H), 6.65 (dd, J = 1.8, 8.1 Hz, 1H, Ar–H), 6.86 (d, J = 8.1 Hz, 1H, Ar–H), 6.94 (d, J = 15.6 Hz, 1H, ═CH), 7.60 (d, J = 15.6 Hz, 1H, CH═), 8.99 (br s, 1H, NH). HRMS found [M – H]⁻ (m/z): 451.1209. Calcd for C₂₀H₂₄N₂O₈S m/z: 452.1253.

About Onconova Therapeutics, Inc.

Onconova Therapeutics is a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer. Onconova's clinical and pre-clinical stage drug development candidates are derived from its extensive chemical library and are designed to work against specific cellular pathways that are important in cancer cells, while causing minimal damage to normal cells. In addition to rigosertib, the Company's most advanced product candidate, two other candidates are in clinical trials, and several candidates are in pre-clinical stages.  For more information, please visit http://www.onconova.com.

NEWTOWN, Pa., Nov. 7, 2013 (GLOBE NEWSWIRE) -- Onconova Therapeutics, Inc. , a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, today announced two presentations relating to clinical trials of its most advance product candidate, rigosertib, at the 55^th American Society of Hematology (ASH) Annual Meeting in New Orleans, Louisiana, December 7-10, 2013. The presentations will include data on efficacy, tolerability, and dosing regimen from the Phase 2 study (ONTARGET) of oral rigosertib in transfusion-dependent, lower risk MDS patients and response, overall survival, and longer-term follow-up data from a Phase 1/2 trial of IV rigosertib in higher risk post-hypomethylating agent treated MDS and AML patients.