Reference Detail

Ref Type

Journal Article

PMID

(37523716)

Authors

Yang L, Tu W, Huang L, Miao B, Kaneshige A, Jiang W, Leng L, Wang M, Wen B, Sun D, Wang S

Title

Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of medicinal chemistry	66	15	2023 Aug 10	10761-10781	J Med Chem

URL

Abstract Text

SMARCA2 is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the design, synthesis, and biological evaluation of selective SMARCA2 protein degraders developed using the proteolysis targeting chimera (PROTAC) technology. Our efforts have led to the discovery of a series of potent and selective SMARCA2 degraders, exemplified by SMD-3040. SMD-3040 degrades SMARCA2 protein with a low nanomolar DC50 and Dmax > 90% and demonstrates an excellent degradation selectivity for SMARCA2 protein over SMARCA4 protein. It displays potent cell growth inhibitory activity in a panel of SMARCA4-deficient cancer cell lines and has much weaker activity in SMARCA4 wild-type cancer cell lines. SMD-3040 achieves strong tumor growth inhibition in two SMARCA4-deficient xenograft models at well-tolerated dose schedules. Further optimization of SMD-3040 may lead to the discovery of new therapies for the treatment of human cancers with SMARCA4 deficiency.

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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
SMD-3040	SMD-3040	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SMD-3040		SMD3040\|SMD 3040		SMD-3040 is a proteolysis-targeted chimera (PROTAC) that binds to SMARCA2 and targets it for degradation, potentially inhibiting cell proliferation and growth of SMARCA4-deficient tumors (PMID: 37523716).

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
SMARCA4 del	melanoma	sensitive	SMD-3040	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SMD-3040 inhibited proliferation of a melanoma cell line with SMARCA4 deletion in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 37523716).	37523716
SMARCA4 del	lung non-small cell carcinoma	sensitive	SMD-3040	Preclinical - Cell line xenograft	Actionable	In a preclinical study, SMD-3040 inhibited proliferation of a non-small cell lung cancer cell line with SMARCA4 deletion in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 37523716).	37523716