Combating KRAS G12D-Driven Tumors: The Antitumor Potential of INCB161734

The KRAS G12D mutation is a prevalent oncogenic driver found in various cancers, notably pancreatic (PDAC) and colorectal (CRC), leading to poor treatment outcomes and highlighting an unmet medical need. This mutation causes continuous activation of key signaling pathways, such as ERK and PI3K, which promote cell proliferation and survival.

INCB161734 is a newly developed, potent, and selective small molecule inhibitor of the KRAS G12D mutation, which is orally bioavailable and has shown significant in vivo efficacy in tumor models carrying the G12D mutation. The compound binds to the G12D mutant with high affinity, regardless of whether it is in the GDP or GTP state, and shows a preference for the mutant form over the wildtype (WT) KRAS by more than 80-fold.

In cellular assays, INCB161734 has demonstrated high selectivity for the G12D mutation and effectively inhibits ERK phosphorylation, a marker of KRAS activity, with a low mean IC50 value. It also suppresses the proliferation of G12D mutant cancer cell lines and induces apoptosis and cell cycle arrest in these cells at much lower concentrations than required for WT cell lines.

The inhibitor exhibits excellent oral bioavailability characterized by favorable absorption, clearance, and metabolic properties. When administered orally, INCB161734 achieves sustained target engagement and nearly complete inhibition of KRAS in G12D tumor xenografts.

Demonstrating its anti-tumor efficacy, INCB161734 has led to significant tumor growth inhibition, arrest, and regression across various PDAC and CRC mouse models. The compound's potential to benefit patients with KRAS G12D-mutated diseases is currently being explored in ongoing clinical trials. These findings indicate INCB161734's promise as a selective KRAS G12D inhibitor with potent anti-tumor activity.