Rearranged during transfection (RET), an oncogenic driver, has been found in multiple tumor types and is thus a promising anticancer therapeutic target. Novel selective RET inhibitors (RETi) that can overcome V804 gatekeeper mutations, endowing resistance to multikinase inhibitors (MKI) and, in particular, achieving KDR selectivity, are needed. In addition, the mechanisms underlying RET–inhibition-induced antiproliferative effects in the context of RET addiction are incompletely understood. This study describes a novel selective RETi, SYHA1815, which inhibited the kinase activity of RET wild type and V804 mutant with an IC50 in the subnanomolar to nanomolar range. Notably, SYHA1815 exhibited approximately 20-fold selectivity for RET over KDR, almost equivalent to that of the launched selective inhibitor pralsetinib. SYHA1815 had only a marginal inhibitory effect on cellular KDR signaling at a high (200 nmol/L) concentration, confirming the selectivity over KDR. In addition, SYHA1815 exhibited a favorable selectivity profile, with greater than 100-fold selectivity for RET over 347 other kinases. It exhibited potent antitumor efficacy and overcame V804 mutations in vitro and in vivo by targeting RET. Then, using SYHA1815 as a probe, we found that RET inhibition suppressed RET-driven cell proliferation via G1 cell-cycle arrest through downregulating c-Myc. Furthermore, disruption of c-Myc upon Brd4 inhibitor treatment led to G1 cell-cycle arrest and overrode RET-driven cell proliferation. Moreover, consistent with the marked in vivo efficacy of RET inhibition, the intratumoral c-Myc level was significantly decreased. In summary, SYHA1815 is a promising RETi for RET-aberrant cancer treatment that is currently in a phase I trial.

中文翻译：

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新型 RET 抑制剂 SYHA1815 通过 c-Myc 下调诱导 G1 细胞周期阻滞来抑制 RET 驱动的癌症并克服守门人突变

转染过程中重排 (RET) 是一种致癌驱动因子，已在多种肿瘤类型中发现，因此是一种有前途的抗癌治疗靶点。需要能够克服 V804 看门人突变、赋予对多激酶抑制剂 (MKI) 的抗性，特别是实现 KDR 选择性的新型选择性 RET 抑制剂 (RETi)。此外，在 RET 成瘾的背景下，RET 抑制诱导的抗增殖作用的机制尚不完全清楚。该研究描述了一种新型选择性RETi，SYHA1815，它抑制RET野生型和V804突变体的激酶活性，IC50在亚纳摩尔至纳摩尔范围内。值得注意的是，SYHA1815 对 RET 的选择性比 KDR 高约 20 倍，几乎与推出的选择性抑制剂 pralsetinib 相当。SYHA1815 在高浓度 (200 nmol/L) 下对细胞 KDR 信号传导仅具有边际抑制作用，证实了对 KDR 的选择性。此外，SYHA1815 表现出良好的选择性，对 RET 的选择性超过 347 种其他激酶的 100 倍以上。它表现出强大的抗肿瘤功效，并通过靶向 RET 在体外和体内克服了 V804 突变。然后，使用 SYHA1815 作为探针，我们发现 RET 抑制通过下调 c-Myc 通过 G1 细胞周期停滞抑制 RET 驱动的细胞增殖。此外，在 Brd4 抑制剂治疗后 c-Myc 的破坏导致 G1 细胞周期停滞并压倒 RET 驱动的细胞增殖。此外，与 RET 抑制的显着体内功效一致，瘤内 c-Myc 水平显着降低。总之，