The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation

doi:10.1158/1535-7163.MCT-21-0127

	The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation
	Jiang, Yuchen 1,2; Peng, Xia 1; Ji, Yinchun 1; Dai, Yang 1; Fang, Yanfen 1; Xiong, Bing 3; Ren, Wenming 3; Hu, Youhong 3; Chen, Yi 1,2; Ai, Jing 1,2
刊名	MOLECULAR CANCER THERAPEUTICS
	2021-11-01
卷号	20 期号:11 页码:2198-2206
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-21-0127
通讯作者	Chen, Yi(ychen@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn)
英文摘要	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 G(1) cell-cycle arrest through downregulating c-Myc. Furthermore, disruption of c-Myc upon Brd4 inhibitor treatment led to G(1) 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.
资助项目	Natural Science Foundation of China[81773762]
WOS关键词	LUNG-CANCER ; OPEN-LABEL ; ACTIVATION ; RECEPTOR ; PHASE-2 ; GENE ; ALK
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000715281700011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298701]
专题	中国科学院上海药物研究所
通讯作者	Chen, Yi; Ai, Jing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Yuchen,Peng, Xia,Ji, Yinchun,et al. The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation[J]. MOLECULAR CANCER THERAPEUTICS,2021,20(11):2198-2206.
APA	Jiang, Yuchen.,Peng, Xia.,Ji, Yinchun.,Dai, Yang.,Fang, Yanfen.,...&Ai, Jing.(2021).The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation.MOLECULAR CANCER THERAPEUTICS,20(11),2198-2206.
MLA	Jiang, Yuchen,et al."The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation".MOLECULAR CANCER THERAPEUTICS 20.11(2021):2198-2206.