Tropomyosin receptor kinase inhibitors: an updated patent review for 2016-2019

Abstract

Introduction: Tropomyosin receptor kinases (Trks) control processes in the fields of growth, survival, and differentiation of neuronal processes. They also play a crucial role in neurodegenerative diseases as well as different types of cancer. Interest in developing Trk inhibitors to target NTRK fusion-driven cancers has escalated in the last decade, leading to the FDA approval of the pan-Trk inhibitors entrectinib and larotrectinib. The development of next-generation inhibitors that overcome resistance mutations arising from treatment with these first generation inhibitors has been the focus in recent years.Area covered: In this updated patent review for 2016-2019, patents covering inhibitors targeting the Trk family are discussed as a continuation of the previous reviews, Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Parts 1 & 2. The status of Trk inhibitors in clinical trials is also evaluated. For the identification of relevant patents and clinical trials, Web of Science, Google, Google Patents, and patent referencing were used.Expert opinion: The FDA approval of larotrectinib and entrectinib is a prime example of how basket clinical trial design targeting oncogenic drivers, regardless of tumor histology, is a viable approach to drug discovery and embodies the shift toward personalized medicine.

Keywords: NTRK; Trk inhibitor; TrkA; TrkB; TrkC; Tropomyosin receptor kinase; allosteric inhibitors; cancer treatment; chronic pain; entrectinib; larotrectinib; resistance mutations; selitrectinib; targeted therapy.