74O - Highly potent and selective RET inhibitors that overcome adaptive drug resistance

Background

RET gene mutation and fusion are the driving events for the generation and deterioration of many cancer types. The first generation RET inhibitors, selpercatinib (Loxo-292) and pralsetinib (Blu-667), demonstrated clinically acquired resistance (e.g., solvent frontier mutations G810X, double mutations V804X-G810X etc.). Novel treatment that overcome multiple resistance mutations is needed to improve patient outcomes. Leveraging our in-house AI technology platform, we have discovered the next generation RET inhibitors that overcome multiple resistance mutations including solvent front, gatekeeper and various double mutations.

Methods

We employ the synergistic advantages of domain expertise and modern technology to accelerate early stage drug discovery. On our deep learning (DL) centric AI platform, extensive scientific computing supports large scale virtual screening, generative design, drug property prediction and multi-objective lead optimization. Only the optimized candidate compounds are passed along for synthesis and testing to save time and cost.

Results

In cell proliferation assays, our compound effectively inhibited KIF5B-RET Ba/F3 WT, V804M, G810S, G810R, V804M-G810S with IC50 values of 0.4 nM, 1.3 nM, 1.1 nM, 3.4 nM, 6.3 nM, respectively, demonstrating significant improvement over selpercatinib in the range of several hundred fold in activities. Importantly, the compound is highly selective against VEGFR, an off-target responsible for cardiovascular adverse effects in the non-selective RET inhibitors. The superior cellular potencies translated consistently into animal models. In Ba/F3 KIF5B-RET-G810R xenograft model, treatment of 25 mg/kg bid resulted in >90% TGI and 100% survival of mice bearing the Ba/F3 KIF5B-RET-G810R tumors. The compound showed favorable pharmacokinetic properties. Preclinical safety evaluations in rats exhibited good tolerance margin.

Conclusions

We have discovered the second generation compounds that potently inhibit a diverse range of RET alterations. The compound has a suitable pharmacological profile and is advancing toward IND application.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

LexBio.

Funding

LexBio.

Disclosure

All authors have declared no conflicts of interest.