A review: recent developments of co-targeted TRK (tropomyosin receptor kinases) inhibitors for cancer therapy.

Multi-targeted agents can sequentially act on two or more targets, leading to synergistic and more effective therapeutic effects against several complicated disorders, containing cancer, even with relatively modest action. The TRKs (tropomyosin receptor kinases) are confirmed as promising targets in anti-tumor drug discovery. Over the past 20 years, many small molecules TRK inhibitors have been identified, that some of them are being investigated in various clinical phases. Also, entrectinib and larotrectinib as TRK inhibitors were approved to treat TRK-fusion positive solid tumors by FDA. Due to drug resistance, potential toxicity and limited clinical efficacy of TRK inhibitors, it is required to achieve new approaches to increase their clinical efficacy. Multi-target therapy, particularly dual-target therapy, is an attractive research topic in cancer therapy that may lead to pharmacokinetic advantages, reduction of toxicity and therapeutic efficacy. Based on many studies, simultaneous inhibition of TRK with other targets, for example ALK, c-Met, RET, IL-2, CSFR1, BDNF, Aurora, FLT3, EGFR and etc. can cause to better and promising therapeutic effects in cancer therapy. In this review, structures, synthetic reactions, biological data and in silico studies of dual-target TRK inhibitors and multi-target TRK inhibitors were summarized. Although studies on this class of compounds are in their early stages and extensive studies on this class of inhibitors are definitely needed, we hope that this review can help in the design of more effective drugs.