Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization

• Published in: European journal of medicinal chemistry Vol. 224; p. 113673
• Main Authors: Li, Mu-Chun, Lin, Wen-Hsing, Wang, Pei-Chen, Su, Yu-Chieh, Chen, Pei-Yi, Fan, Chu-Min, Chen, Ching-Ping, Huang, Chen-Lung, Chiu, Chun-Hsien, Chang, Ling, Chen, Chiung-Tong, Yeh, Teng-Kuang, Hsieh, Hsing-Pang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.11.2021; Elsevier
• Subjects: Chemistry, Medicinal; Fusion; Kinase inhibitor; Life Sciences & Biomedicine; Mutation; Pharmacology & Pharmacy; Property-driven optimization; Science & Technology; Tropomyosin receptor kinase (TRK); Mutation; Tropomyosin receptor kinase (TRK); Kinase inhibitor; Fusion; Property-driven optimization; METASTASIS; ACQUIRED-RESISTANCE; IDENTIFICATION; CANCER; DISCOVERY; ONCOGENE; RECEPTOR TYROSINE KINASES; ENTRECTINIB; AURORA KINASES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113673

Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74–151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor. [Display omitted] •A next-generation orally selective type II TRK inhibitor was discovered.•Twenty-nine quinazoline-based analogues were designed and synthesized.•Property-driven strategy guided lead-to-candidate optimization.•39 is a potent TRK inhibitor against both wild-type and mutant TRKs.•39 demonstrated antitumor effectiveness in KM-12 xenograft model.