TSN1611: Targeting KRASG12D Mutations in Cancer with a Novel Potent and Selective Inhibitor

KRAS gene mutations are a common driver of cancer, found in about a quarter of all human cancers, with the KRASG12D variant being particularly prevalent in pancreatic, colorectal, and non-small cell lung cancers (NSCLC). Inhibiting KRASG12D is challenging due to the lack of a suitable amino acid residue for irreversible binding by a ligand. TSN1611 is a newly developed inhibitor that selectively targets the KRASG12D mutation, showing promising oral pharmacokinetics and significant anti-tumor effects in relevant cancer models.

The study utilized a biochemical HTRF assay to measure TSN1611's inhibitory effects on both the GDP-bound and GTP-bound states of KRASG12D. The binding affinity was further assessed using a biophysical SPR method. Cellular activity was evaluated through in vitro cell proliferation assays with Ba/F3 cells modified to carry the KRASG12D mutation and other tumor cell lines with the same mutation. Xenograft models derived from human cancer cells, HPAC (pancreatic) and GP2D (colorectal), were employed to assess in vivo antitumor effects. Pharmacokinetic studies were conducted in mice, rats, and dogs, along with nonclinical safety evaluations to determine the toxicity profile.

TSN1611 was found to inhibit both the active and inactive forms of the KRASG12D protein with high potency, and it showed excellent selectivity over other RAS family members and KRAS isoforms. The compound demonstrated dose-dependent anti-tumor efficacy in the GP2D and HPAC models, with its mechanism of action confirmed to be the inhibition of the KRAS signaling pathway. TSN1611's oral bioavailability and safety across multiple species were also established.

In conclusion, TSN1611 is a selective inhibitor of the KRASG12D mutation, exhibiting high selectivity and activity in both in vitro and in vivo studies. It also displayed favorable physicochemical properties, oral pharmacokinetics, and potential for brain penetration. The compound has shown acceptable safety margins, and the preclinical data supports its further development. A phase I/II study is planned for the first half of 2024, subject to regulatory approval.