9e1k
From Proteopedia
Discovery of Potent, Highly Selective and Efficacious SMARCA2 Degraders - Compound 11
Structural highlights
DiseaseSMCA2_HUMAN Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358. A rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time.[1] [2] FunctionSMCA2_HUMAN Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).[3] Publication Abstract from PubMedWe describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-a]quinazolin-5(7H)-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. We further highlight the optimization of the pharmacokinetic profile of a subset of compounds leading to potent and selective degradation of SMARCA2 in the xenograft model. These compounds provide valuable tools with desirable properties for continued exploration of the biology defining the susceptibility of SMARCA4 mutant cancers to selective loss of SMARCA2. Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.,Li Z, Harikrishnan LS, Xu G, Samanta D, Clemente JC, Leng L, Tu W, Yang L, Huang L, Wang M, Wang S, Deng Q, Behshad E, Nagilla R, Orth P, Rice C, Strickland C, Mohammad HP, Priestley ES, Sui Z J Med Chem. 2024 Nov 21. doi: 10.1021/acs.jmedchem.4c01878. PMID:39570797[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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