Garsorasib

Garsorasib is an inhibitor of K-Ras containing the activating glycine-to-cysteine mutation at position 12 (K-RasG12C, IC50 = 18 nM). It selectively binds to GDP-bound K-RasG12C over GDP-bound wild-type K-Ras in thermal shift assays and selectively inhibits ERK phosphorylation in NCI H358 cells, which express K-RasG12C, over NCI H1993 cells, which express wild-type K-Ras (IC50s = 6.9 and >1,000 nM, respectively). Garsorasib inhibits proliferation in 11 K-RasG12C-expressing cancer cell lines (IC50s = 4.6-33 nM) but not in K-RasG12D- or wild-type-expressing cancer cells (IC50s = >10,000 nM). In vivo, garsorasib (30 mg/kg) induces tumor regression in NCI H358 non-small cell lung cancer (NSCLC) and MIA PaCa-2 pancreatic cancer mouse xenograft models. InChI: InChI=1S/C32H32F2N8O2/c1-4-24(43)40-13-17(3)41(14-16(40)2)30-20-12-22(34)28(25-21(33)6-5-7-23(25)35)38-31(20)42(32(44)39-30)29-26(18-8-9-18)36-15-37-27(29)19-10-11-19/h4-7,12,15-19H,1,8-11,13-14,35H2,2-3H3/t16-,17+/m1/s1 InChIKey: DKFRWZJCNPETGI-SJORKVTESA-N SMILES: O=C1N(C2=NC(C3=C(C=CC=C3N)F)=C(F)C=C2C(N4[C@H](CN([C@@H](C4)C)C(C=C)=O)C)=N1)C5=C(C6CC6)N=CN=C5C7CC7