Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Published: August 2023
AI Article Synopsis
Article Abstract
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 DC and > 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.
Unlabelled: Sinonasal carcinomas are aggressive neoplasms that present a high morbidity and mortality rate with an unfavorable prognosis. This group of tumors exhibits morphological and genetic diversity. Genetic and epigenetic alterations in these neoplasms are the current targets for diagnosis and treatment.
We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines.
Scientists found mutations in some important parts of a protein complex related to lung cancer.
They created a new drug called YD23 that targets a specific part of this complex to help fight cancer cells.
Testing showed that YD23 can slow down tumor growth in cells that have the mutations, which could help develop better treatments for certain lung cancers.
Genetic mutations and epigenetic changes work together to promote cancer by impacting cancer-related genes, particularly the SWI/SNF complex members SMARCA4 and SMARCA2.
The simultaneous loss of both SMARCA4 and SMARCA2 is notably lethal and is a distinctive characteristic in specific cancers like early-onset ovarian cancer and other rare tumors.
The review explores the common clinical and molecular traits of cancers with this dual loss, the mechanisms leading to their dysfunction, and potential targeted therapies for these conditions.*
Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identified to be synthetic lethal to indicating SMARCA2 is a high value therapeutic target. Here, we disclose the discovery and characterization of potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs.
