21:I[432972,["/_next/static/chunks/bb923814e1f4d2e9.js","/_next/static/chunks/dd3ee9f5b7716ca6.js","/_next/static/chunks/4204a0ae82542ca8.js","/_next/static/chunks/30036bedc5269936.js","/_next/static/chunks/6e1aa89a642f40be.js","/_next/static/chunks/cd5e572bc3e4eb92.js","/_next/static/chunks/8ffd0b71567920d8.js","/_next/static/chunks/67ea6dfd21f16c5f.js","/_next/static/chunks/24eb4379f68013fd.js","/_next/static/chunks/b8cd775ffdf935bd.js","/_next/static/chunks/983103cd9eb7b428.js","/_next/static/chunks/d4ac9dcf27f6ff52.js","/_next/static/chunks/294b9525248c8e5f.js"],"default"] 22:T49a,Tropomyosin receptor kinase (TRK) secondary mutations mediating acquired resistance, especially at the solvent-front (SF) and the DFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinase inhibitors have displayed significant advantages in overcoming clinical resistance driven by kinase mutations; however, all reported small-molecule macrocyclic TRK inhibitors are all type I inhibitors and are therefore much more sensitive to SF than xDFG mutations. Novel therapeutics for patients with xDFG resistance mutations are urgently needed. We report the first highly selective macrocycle-based potent type II TRK inhibitor, 7b, that exhibits high inhibitory potency toward various TRK fusion protein variants as well as wild type. 7b exhibited potent antiproliferative activity against Ba/F3 cells harboring CD74-TRKA^G667C and ETV6-TRKC^G696C with half-maximum inhibitory concentration (IC₅₀) values of 6 and 1.7 nM, respectively. More importantly, 7b also showed potent antiproliferative activity against a panel of SF mutants (IC₅₀ = 5.6-110 nM) and displayed extraordinary kinome selectivity.23:T488,The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKA^G595R, TRKA^G667C_, and TRKA^F589L with IC₅₀ values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC₅₀ values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1^G595R and BaF3-CD74-NTRK1^G667C xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.24:T6e0,

#	Concept	H-Index	Publications	Citations
1	Medicine	3	3	42
2	Pathology	2	2	26
3	Natural Sciences	1	1	16
4	Cell Biology	1	1	12
5	Chemical Biology	1	1	16

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