Pan KRas-IN-1

• CAT Number: I042891
• CAS Number: 2791263-84-6
• Molecular Formula: C33H36F3N5O3
• Molecular Weight: 607.67
• Purity: ≥95%
• Synonyms: (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methylpiperidin-3-ol
• InChI: InChI=1S/C33H36F3N5O3/c1-3-22-25(35)7-6-19-12-21(42)13-23(26(19)22)28-27(36)29-24(15-37-28)30(40-10-4-8-32(2,43)17-40)39-31(38-29)44-18-33-9-5-11-41(33)16-20(34)14-33/h6-7,12-13,15,20,42-43H,3-5,8-11,14,16-18H2,1-2H3/t20-,32-,33+/m1/s1
• InChIKey: RZYWNBKMTZABBP-PAXFXPPDSA-N
• SMILES: CCC1=C(C=CC2=CC(=CC(=C21)C3=NC=C4C(=C3F)N=C(N=C4N5CCCC(C5)(C)O)OCC67CCCN6CC(C7)F)O)F

Pan KRas-IN-1 is a pan KRas inhibitor, can be used for agent resistance in cancer developed with KRas G12C inhibitors[1].
Pan KRas-IN-1 (example 5) shows high binding capacity to KRas, with IC50s of <2 nM among different KRas isform, including G12D, G12V, G12R, G12A, G12S, G13D, Q61H, and WT[1]. Pan KRas-IN-1 inhibits the phosphorylation of ERK downstream of KRas in different cells; AsPC-1 (G12D, IC50=9 nM), A549 (G12S, IC50=11 nM), HCT116 (G13D, IC50=23 nM), NCI-H358 (G12C, IC50=6 nM), NCI-H460 (Q61H, IC50=12 nM), NCI-H727 (G12V, IC50=29 nM), MKN1 (WT, IC50=32 nM), PSN-1 (G12R, IC50=681 nM)[1]. Pan KRas-IN-1 (0-3000 nM; 5 d) exhibits anti-proliferative activity against mutation of reststance to Adagrasib (HY-130149, MRTX849) in mouse 3T3 fibroblasts, with IC50s of 32 nM (G12A), 28.1 nM (G12C), 20.25 nM (G12D), 1742 nM (G12R), 94 nM (G12V), 50 nM (G12W), 610 nM (G13D), 58 nM (Q61H)[1].

Reference

[1]. Wang Xiaolun, et al. Preparation of azaquinazoline pan-KRas inhibitors: World Intellectual Property Organization, WO2022132200[P]. 2022-06-23.