Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	11	2021 11	2198-2206	Mol Cancer Ther

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
SYHA1815	SYHA1815	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SYHA1815		SYHA-1815\|SYHA 1815	RET Inhibitor 52	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