Tuesday, June 2, 2015

Drugs in Clinical Pipeline: SAR125844

SAR125844 [1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea] is a potent and selective small molecule inhibitor of MET receptor tyrosine kinase with potential therapeutic application in cancer patients having deregulated MET-dependent malignancies. SAR125844 displayed nanomolar activity against the wild-type MET kinase (IC50 = 4.2 nM) and the M1250T and Y1235D mutants [1,4]. 

Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase in a panel of 275 kinases tested, with only 5 other protein kinases inhibited at IC50 values below 300 nM (CDK9 greater than 10 uM). SAR125844 exhibits also satisfactory eADMET in vitro properties and has shown moderate total plasma clearance, large volume of distribution and moderate to long terminal elimination half-life in rats.

SAR125844 is a Biopharmaceutics Classification System (BCS) class IV due to its very poor solubility in water (less than 0.1 µg mL) and poor permeability characteristics, thus developed for intravenous administration to overcome the permeability issue. In vitro it has highly potent nanomolar anti-proliferative activity on human Met- driven tumor cell lines exclusively. The cellular anti-tumor activity as a single agent in human Met-amplified models is also highly potent [2].

Common Name: SAR125844
Synonyms: SAR125844; SAR 125844; SAR-125844
IUPAC Name: 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea
CAS Number: 1116743-46-4
Mechanism of Action: MET Kinase Inhibitor
Indication: Various Cancers; Anti-Tumor Therapy
Development Stage: Phase I
Company: Sanofi

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

In cellular assays, SAR125844 inhibits MET autophosphorylation at the nanomolar range (IC50 from 1.4 to 5.1 nM), translating into antiproliferative activity selectively in MET-driven cell lines such as MET-amplified cell lines, with IC50 values in the low nanomolar range and induction of apoptosis. SAR125844 induces a G1 block in the two MET-amplified tumor cell lines tested. Moreover, the compound is also able to inhibit HGF-induced cell migration in PC-3 prostate tumor cell line. In two MET-amplified human gastric tumor xenograft models tested, SNU-5 and Hs 746T, SAR125844 intravenous treatment leads to potent impact on the MET signaling pathway in a dose and time dependent manner, with potent inhibition of MET autophosphorylation, as well as a significant effect on downstream PI3K/AKT and RAS/MAPK pathways. As a single agent, this translates into a dose-dependent antitumor activity in these two xenograft models, with tumor stasis at the lowest active dose and tumor regression at the highly active doses. High loading single dose administration of SAR125844 using a nanosuspension formulation allowed a sustained P-MET inhibition in tumors up to 7 days. In all models, antitumor activity was achieved at well tolerated doses without significant effect on body weight [3,4].

1. Schio, J.; et. al. Abstract 2911: SAR125844: a potent and selective ATP-competitive inhibitor of MET kinase. Cancer Res 2012, 72, 2911.
2. Authelin, J.-R.; et. al. Anti-tumoral composition comprising the compound 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea. WO2014009500A1.
3. Goulaouic, H.; et. al. Abstract 845: In vitro and in vivo pharmacology of SAR125844, a potent and selective intravenous MET kinase inhibitor undergoing Phase I clinical trial. Cancer Res 2012, 72, 845.
4. Goulaouic, H.; et. al. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. Mol Cancer Ther 2015, 14(2), 384-394.