BBO-11818：一种口服生物利用度良好、高效且选择性的非共价泛KRAS(ON)和(OFF)抑制剂，在KRAS突变临床前模型中具有强劲的抗肿瘤活性

KRAS is commonly mutated in human cancer. Inhibitors of KRAS G12C have shown promising clinical efficacy; however, there are currently no approved targeted therapies against other KRAS variants, and a significant underserved patient population across several major cancer types, including pancreatic carcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC), remains. We discovered BBO-11818: a potent, selective, orally bioavailable small molecule KRAS inhibitor with activity against multiple KRAS mutants, including KRAS G12D and KRAS G12V , in both their active GTP-bound (ON) and inactive GDP-bound (OFF) states. BBO-11818 binds the switch II pocket with high affinity and selectivity, locking the active form in the signaling-incompetent state 1 to disrupt the association of GTP-bound KRAS with its key effector RAF1, and sequestering the inactive form. BBO-11818 potently inhibits several oncogenic KRAS mutants in cell-based assays, resulting in the suppression of MAPK signaling and inhibition of cell proliferation with single-digit nanomolar EC 50 values. The selectivity of BBO-11818 for KRAS is demonstrated by its >1000-fold lower potency against NRAS- and BRAF-mutant cell lines. BBO-11818 exhibits favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties in mouse models of cancer. Single dose, oral administration results in strong dose- and time-dependent inhibition of pERK in KRAS G12D and KRAS G12V cell-derived xenograft (CDX) models. BBO-11818 monotherapy induces strong anti-tumor responses, including regression at well-tolerated doses in CDX and patient-derived xenograft (PDX) models of KRAS-mutant PDAC, NSCLC, and CRC. Combination treatment with BBO-10203, a clinical-stage (NCT06625775), selective RAS:PI3Kalpha breaker that blocks RAS-mediated activation of the PI3Kalpha-AKT pathway, results in decreased cellular proliferation, increased apoptosis, and enhanced efficacy in CDX and PDX models harboring KRAS G12D or KRAS G12V mutations. Similarly, combination treatment with BBO-11818 and cetuximab, an approved anti-EGFR monoclonal antibody, results in enhanced anti-tumor activity in a KRAS G12D CDX model. Finally, BBO-11818 shows combination benefit with anti-PD-1, resulting in complete tumor regressions in the KRAS G12D CT-26 syngeneic tumor mouse model. BBO-11818 is a potent pan-KRAS inhibitor with activity against both the GTP- and GDP-bound states of KRAS, presenting the opportunity to address a large fraction of KRAS-mutant tumors currently lacking targeted therapeutic options. BBO-11818 has entered Phase 1 clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079).