ARS-1620

KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles.

Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line...Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.

Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents.

Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively...Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.

Above genes were relevant to tumor cell resistance to targeted therapy. This study provides important insights into the molecular mechanisms underlying tumor cell resistance to KRAS inhibitor treatment.

Gene expression studies revealed that MAPK expression is strongly correlated with decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. These results indicate that our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales.

A series of novel quinazoline analogs were designed and synthesized based on ARS-1620 and LLK-10 (a KRAS inhibitor reported by us recently) as KRAS G12C inhibitors with a 5-nitrofuran-2-carboxylic acid warhead...Lastly, KS-19 possessed a benign toxicity profile without causing bone marrow suppression and any obvious morphological abnormalities in major organs of mice. Collectively, these results suggest that KS-19 represents a novel inhibitor of KRAS G12C worthy of further investigation as a potential anticancer agent.

In H358 lung carcinoma cells, IDO1 expression induced by IFN-γ was at least in part dependent on ERK activation, and treatment with ARS-1620, a covalent KRas inhibitor, suppressed IDO1 expression induced by IFN-γαμμα in a concentration-dependent manner...In addition, KRas downregulation by specific siRNAs decreased IFN-γ-induced IDO1 expression in A549 lung cancer cells. Taken together, our study strongly suggests that Ras/ERK signaling pathway plays an important role in promoting IDO1 expression induced by IFN-γ.

Lastly, K20 exhibited benign toxicity profiles without causing bone marrow suppression and any other apparent toxicity to major organs of mice. Collectively, these results indicate that K20 is a KRas G12C inhibitor deserving further investigation.

In H358 lung carcinoma cells, IDO1 expression induced by IFN-γ was at least in part dependent on ERK activation, and treatment with ARS-1620, a covalent KRasG12C inhibitor, suppressed IDO1 expression induced by IFN-γ in a concentration-dependent manner...In addition, KRas downregulation by specific siRNAs decreased IFN-γ-induced IDO1 expression in A549 lung cancer cells. Taken together, our study strongly suggests that Ras/ERK signaling pathway plays an important role in promoting IDO1 expression induced by IFN-γ.