9NTB

Crystal structure of human HDAC2 in complex with TNG260

This is a non-PDB format compatible entry.

Summary for 9NTB

• Entry DOI: 10.2210/pdb9ntb/pdb
• Descriptor: Histone deacetylase 2, (R)-N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(S-methylsulfonimidoyl)benzamide, ZINC ION, ... (10 entities in total)
• Functional Keywords: inhibitor, zinc metalloenzyme, hdac1, corest, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 143004.86

Authors

McMillan, B.J.,Whittington, D.A. (deposition date: 2025-03-18, release date: 2025-09-17, Last modification date: 2025-10-29)

Primary citation

Ahronian, L.G.,Sahu, S.,Zhang, M.,Patel, A.S.,Geng, K.,Bhattacharya, R.,Falchook, G.S.,Goldman, J.W.,Spira, A.I.,Punekar, S.R.,Spigel, D.R.,Wang, J.S.,Skoulidis, F.,Stephens, J.,Meynardie, M.,Powell, J.M.,Lopez, A.,Ranieri, M.,Ploszaj, M.A.,Tan, Y.J.,Lee, Y.T.,Yu, Y.,Deng, J.,Chen, T.,McCarren, P.,Tsai, A.,Hussain, S.S.,Doyon, B.,Amemiya, K.,Ermolieff, J.,Shahagadkar, P.,Das, N.M.,Flynn, L.R.,Shields, J.A.,Danielczyk, L.,McMillan, B.J.,Mignault, A.,Meier, S.R.,Wu, H.J.,Guerin, D.J.,Whittington, D.A.,Min, C.,Sienczylo, I.,Maxwell, J.P.,DiBenedetto, H.J.,Watanabe, H.,Haines, B.B.,Huang, A.,Crystal, A.,Andersen, J.N.,Wu, X.,Wong, K.K.
TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes STK11-Mutant Tumors to Anti-PD-1 Immunotherapy.
Cancer Res., 85:3966-3982, 2025

PubMed Abstract: Patients with non-small cell lung cancer (NSCLC) with loss of the tumor suppressor gene STK11 are resistant to immune checkpoint therapies like anti-PD-1. In this study, we conducted an in vivo CRISPR screen that identified histone deacetylase 1 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 in 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 patients with STK11-mutant NSCLC.

PubMed: 40882030
DOI: 10.1158/0008-5472.CAN-25-0998

Experimental method

X-RAY DIFFRACTION (1.8 Å)