Discovery of BMS-986449: A Potent, Selective Degrader of the Transcription Factors IKZF2 (Helios) and IKZF4 (Eos) to Target Regulatory T Cells in Solid Tumors.

Authors

Emily C Cherney, Satheesh K Nair, Suresh Babu Viswa Krishna Penmetsa, Bharat Shimpukade, Audris Huang, Donna Bilder, Andrew P Degnan, Godwin K Kumi, Liping Zhang, Ashok V Purandare, Fukang Yang, Guo Li, Weifang Shan, Yan Chen, Shuqun Lin, Peter Park, Dharmpal S Dodd, Durgarao Kantheti, Sivaramakrishna Padamata, Raju K V L P Manepalli, Naga Malleswara Reddy Sirigireddy, Malappa Malappa, T G Murali Dhar, Cullen L Cavallaro, Ling Li, Martins S Oderinde, Daniel Smith, Joseph M Pawluczyk, James Kempson, Muthalagu Vetrichelvan, Anuradha Gupta, Arvind Mathur, Richard Rampulla, Carolyn A Weigelt, Sirish Kaushik Lakkaraju, Purnima Khandelwal, Madhu Katepalli, Thaiya Nachiar K Lenin, Stephan Riedmaier, Keith DiPetrillo, Kimberly A Foster, Mohan Krishna Rayeni, Vikas Choure, Torsa Das, Steven Levine, Monica Kwok, Mary Ellen Cvijic, Xin Li, Hua Fang, Debarati Mazumder Tagore, Madhu Sudhan Ravindran, Sheetal R Gujaran, Anupama Natarajan, Jinyi Zhu, Barbra Pagarigan, Pavan Srinivas, Ari Salinger, Ashok R Dongre, Harris Bell-Temin, Helen Pham, Pathik Rakesh Desai, Olivia Calder, Lihong Shi, Sixuan Guo, Godrej Khambatta, Pallavur Sivakumar, Nadia Ladygina, Rama Krishna Narla, Gopal Dhar, Aravind Anandam, Vidhi Khanna, Shailesh Dudhgaonkar, Jinqi Liu, Michael J Barnes, Robert Borzilleri, Louis J Lombardo, Gregory Vite, John T Hunt, Aaron Balog

Published in

Journal of medicinal chemistry. Aug 26, 2026. Epub Aug 26, 2026.

Abstract

Within the tumor microenvironment (TME), regulatory T (Treg) cells promote an immunosuppressive state with limited tumor antigen presentation and antitumor effector T (Teff) cell responses, which can drive resistance to cancer immunotherapies. IKZF2 (Helios) is a transcription factor essential for stabilizing the immunosuppressive Treg cell phenotype in tumors. Herein, we present the discovery of BMS-986449, a selective Cereblon E3 Ligase Modulatory Drug (CELMoD) degrader of IKZF2 and IKZF4 (Eos) that spares the closely related transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos). BMS-986449 is an orally available degrader that demonstrates single-agent growth inhibition of syngeneic MC38 tumors implanted in humanized Cereblon (CRBN) knock-in mice. Tumor growth inhibition was more robust when BMS-986449 was administered in combination with anti-PD-1. Nonhuman primates administered daily with BMS-986449 show sustained IKZF2 degradation in Treg cells providing confidence in human clinical doses. Collectively, these findings establish BMS-986449 as a promising clinical candidate for cancer immunotherapy.

PMID:
42677819
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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