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Ref Type Journal Article
PMID (34518294)
Authors Jiang Y, Peng X, Ji Y, Dai Y, Fang Y, Xiong B, Ren W, Hu Y, Chen Y, Ai J
Title The Novel RET Inhibitor SYHA1815 Inhibits RET-Driven Cancers and Overcomes Gatekeeper Mutations by Inducing G1 Cell-Cycle Arrest through c-Myc Downregulation.
Journal Molecular cancer therapeutics
Vol 20
Issue 11
Date 2021 11
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
SYHA1815 SYHA-1815|SYHA 1815 RET Inhibitor 47 SYHA1815 is a selective RET inhibitor with activity against RET V804 mutants, potentially leading to inhibition of cell proliferation and tumor growth (PMID: 34518294).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634W thyroid gland medullary carcinoma sensitive SYHA1815 Preclinical - Cell line xenograft Actionable In a preclinical study, SYHA1815 treatment inhibited RET signaling and proliferation of a medullary thyroid cancer cell line harboring RET C634W in culture, and induced tumor regression in a cell line xenograft model (PMID: 34518294). 34518294