Preclinical evaluation of SIM1803-1A, a small molecule Trk/ROS1 dual inhibitor for wild and mutate NTRK/ROS1 fusion solid malignancies.

Abstract

e21663 Background: Fusions and rearrangements of NTRK1/2/3 and ROS1 genes are oncogenic drivers in multiple solid malignancies. Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%). However, the treatment-related drug resistance, including S.F. mutations, G.K. mutations and DFGx mutations, has been identified in clinical trials. The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases. Here we report a novel potent Trk/ROS1 dual inhibitor SIM1803-1A, targeting both the wild type and multiple clinical mutations of Trk and ROS1 with clean selectivity profile and expected in vitro and in vivo efficacy for wild and mutant NTRK/ROS1 fusion solid tumors. Methods: Kinase inhibiting potency was determined with Reaction Biology kinase assays. Kinase selectivity was screened on Eurofins Kinase Profiler panel. Cellular anti-proliferative potency was evaluated on relevant fusion cell lines. Antitumor efficacy was evaluated in the related CDX and PDX mice models shown in results. Results: SIM1803-1A displayed high kinase inhibiting potency with IC50 3.64/1.24 /4.45 nM on TrkA( WT/G595R/G667C) kinase, 0.07/5.03/5.68 nM on TrkC( WT/G623R/L686M), and 0.08/0.10 nM on ROS1( WT/G2032R) respectively. A clean selectivity profile was also identified in 112 enzymes from TK and TKL family at 0.5 µM. The proliferation inhibition IC50 of SIM1803-1A in following cell lines were: 0.3 nM on KM12 TPM3-NTRK1, 2.2/0.9/5.7/5.6 nM on Ba/F3 LMNA-NTRK1( WT/F589L/G595R/G667A), 2.9/6.2 nM on Ba/F3 ETV6-NTRK3( WT/G623R), and 7.3/15.0 nM on Ba/F3 SLC34A2-ROS1(WT/G2032R) respectively. SIM1803-1A showed high antitumor efficacy in the subcutaneous colon cancer KM12 TPM3-NTRK1 CDX model with 68% and 80% TGI at 1 and 3 mg/kg (bid) dosing, and similar high efficacy in the subcutaneous NSCLC LU-01-0414 SDC4-ROS1 PDX model with 60% and 74% TGI at 1 and 3 mg/kg (bid) dosing. Conclusions: Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies.