(S)-JDQ-443

• CAT Number: I042010
• CAS Number: 2653994-10-4
• Molecular Formula: C29H28ClN7O
• Molecular Weight: 526.03
• Purity: ≥95%
• Synonyms: 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one
• InChI: InChI=1S/C29H28ClN7O/c1-5-24(38)36-14-29(15-36)10-20(11-29)37-17(3)25(26-21-13-31-33-22(21)8-16(2)27(26)30)28(34-37)18-6-7-23-19(9-18)12-32-35(23)4/h5-9,12-13,20H,1,10-11,14-15H2,2-4H3,(H,31,33)
• InChIKey: AZUYLZMQTIKGSC-UHFFFAOYSA-N
• SMILES: CC1=CC2=C(C=NN2)C(=C1Cl)C3=C(N(N=C3C4=CC5=C(C=C4)N(N=C5)C)C6CC7(C6)CN(C7)C(=O)C=C)C

(S)-JDQ-443 is an isomer of JDQ-443 (HY-139612). JDQ-443 is an orally active, potent, selective, and covalent KRAS G12C inhibitor (extracted from patent WO2021120890A1). JDQ-443 shows antitumor activity[1][2].
JDQ-443 promotes dose-dependent reductions of phosphorylated ERK (pERK) levels and the proliferation of the KRASG12C-mutated cell lines NCI-H358 and NCI-H2122, with IC50 values of 0.018 and 0.063 μM, respectively[2].
JDQ443 covalently and selectively binds and inhibits GDP-bound KRASG12C with low reversible binding affinity to the RAS switch II pocket, and also inhibits proliferation of KRASG12C-mutated and KRAS G12C/H95, G12C/R68S, and G12C/Y96 double-mutant cell lines[2].
JDQ443 (10-100 mg/kg, Orally, daily for 14 days) shows antitumor activity and inhibits the growth of tumor in a dose-dependent manner in KRAS G12C-mutated CDX models[2]. JDQ443 (Orally, 100 mg/kg, daily (JDQ443) + 7.5 mg/kg, twice daily (TNO155), for 36 days) shows greater cell growth inhibition or cell killing compared with single-agent JDQ443 when combined with TNO155[2]. JDQ443 generates categorical antitumor responses in PDX models of NSCLC and colorectal tumors that are improved by combination treatment with other agents[2].

Reference

[1]. LIU BO, et al. PYRAZOLYL DERIVATIVES USEFUL AS ANTI-CANCER AGENTS. Patent WO2021120890A1.

[2]. Weiss A, Lorthiois E, Barys L, et al. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent and Selective, Covalent Oral Inhibitor of KRASG12C. Cancer Discov. 2022;candisc.0158.2022.
 [Content Brief]