Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810 R/S/C). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RETG810R, RETG810S, and RETG810C) with low nanomolar range (IC50 of 5.7–8.3 nM), which was 15−29-fold more potent than selpercatinib (IC50 of 95.3–244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RETWT-derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RETG810R-positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib.

中文翻译：

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发现 7-（1-甲基-1H-吡唑-4-基）-1,6-萘啶衍生物作为转染过程中重排 （RET） 的有效抑制剂和 RET 溶剂前沿突变体，用于克服 selpercatinib 耐药性


转染激酶 （RET） 抑制过程中的重排被认为是治疗多种癌症的一种有前途的治疗方法。然而，第二代 RET 抑制剂 selpercatinib 的临床治疗益处因溶剂前沿突变（例如 RETG810 R/S/C）介导的获得性耐药而大大受到影响。在此，我们报道了一类 7-（1-甲基-1H-吡唑-4-基）-1,6-萘啶衍生物作为克服 selpercatinib 耐药性的有效 RET 和 RET 溶剂前沿突变抑制剂。代表性化合物 20p 对溶剂前沿突变 （RETG810R、RETG810S 和 RETG810C） 表现出优异的体外抑制活性，具有低纳摩尔范围 （IC50 为 5.7-8.3 nM），比 selpercatinib 强 15-29 倍 （IC50 为 95.3-244.1 nM）。此外，20p 表现出可接受的药代动力学特性，口服生物利用度为 30.4%。重要的是，20p 在 Ba/F3-KIF5B-RETWT 衍生的异种移植小鼠模型和 selpercatinib 耐药的 Ba/F3-KIF5B-RETG810R 阳性突变异种移植小鼠模型中都表现出令人印象深刻的抗肿瘤效力。总体而言，20p 代表了一种新颖且有前途的药物先导物，用于克服 RET 溶剂前沿突变对 selpercatinib 的耐药性。