9ntb
From Proteopedia
Crystal structure of human HDAC2 in complex with TNG260
Structural highlights
FunctionHDAC2_HUMAN Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.[1] Publication Abstract from PubMedNon-small cell lung cancer (NSCLC) patients with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. Here, we conducted an in vivo CRISPR screen that identified HDAC1 as a target to reverse anti-PD-1 resistance driven by loss of STK11 and developed TNG260, a potent small-molecule inhibitor of the CoREST complex with selectivity exceeding previously generated inhibitors in this class in preclinical studies. Treatment with TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells. When combined with anti-PD-1, TNG260 induced immune-mediated stasis and/or regression in STK11-deficient syngeneic tumor models and autochthonous NSCLC models. In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients. TNG260 is a Small-Molecule CoREST Inhibitor that Sensitizes STK11-Mutant Tumors to Anti-PD-1 Immunotherapy.,Ahronian LG, Sahu S, Zhang M, Patel AS, Geng K, Bhattacharya R, Falchook GS, Goldman JW, Spira AI, Punekar SR, Spigel DR, Wang JS, Skoulidis F, Stephens J, Meynardie M, Powell JM, Lopez A, Ranieri M, Ploszaj MA, Tan YJ, Lee YT, Yu Y, Deng J, Chen T, McCarren P, Tsai A, Hussain SS, Doyon B, Amemiya K, Ermolieff J, Shahagadkar P, Das NM, Flynn LR, Shields JA, Danielczyk L, McMillan BJ, Mignault A, Meier SR, Wu HJ, Guerin DJ, Whittington DA, Min C, Sienczylo I, Maxwell JP, DiBenedetto HJ, Watanabe H, Haines BB, Huang A, Crystal A, Andersen JN, Wu X, Wong KK Cancer Res. 2025 Aug 29. doi: 10.1158/0008-5472.CAN-25-0998. PMID:40882030[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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