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DOI 10.1021/acs.jmedchem.6c01271

Медицинская библиотека · Journal of medicinal chemistry · 2026

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.

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

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Аннотация

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.

Для цитирования: Cherney Emily C, Nair Satheesh K, Penmetsa Suresh Babu Viswa Krishna, Shimpukade Bharat, Huang Audris, Bilder Donna, Degnan Andrew P, Kumi Godwin K, Zhang Liping, Purandare Ashok V, Yang Fukang, Li Guo, Shan Weifang, Chen Yan, Lin Shuqun, Park Peter, Dodd Dharmpal S, Kantheti Durgarao, Padamata Sivaramakrishna, Manepalli Raju K V L P, Sirigireddy Naga Malleswara Reddy, Malappa Malappa, Murali Dhar T G, Cavallaro Cullen L, Li Ling, Oderinde Martins S, Smith Daniel, Pawluczyk Joseph M, Kempson James, Vetrichelvan Muthalagu, Gupta Anuradha, Mathur Arvind, Rampulla Richard, Weigelt Carolyn A, Lakkaraju Sirish Kaushik, Khandelwal Purnima, Katepalli Madhu, Lenin Thaiya Nachiar K, Riedmaier Stephan, DiPetrillo Keith, Foster Kimberly A, Rayeni Mohan Krishna, Choure Vikas, Das Torsa, Levine Steven, Kwok Monica, Cvijic Mary Ellen, Li Xin, Fang Hua, Tagore Debarati Mazumder, Ravindran Madhu Sudhan, Gujaran Sheetal R, Natarajan Anupama, Zhu Jinyi, Pagarigan Barbra, Srinivas Pavan, Salinger Ari, Dongre Ashok R, Bell-Temin Harris, Pham Helen, Desai Pathik Rakesh, Calder Olivia, Shi Lihong, Guo Sixuan, Khambatta Godrej, Sivakumar Pallavur, Ladygina Nadia, Narla Rama Krishna, Dhar Gopal, Anandam Aravind, Khanna Vidhi, Dudhgaonkar Shailesh, Liu Jinqi, Barnes Michael J, Borzilleri Robert, Lombardo Louis J, Vite Gregory, Hunt John T, Balog Aaron. 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.. Journal of medicinal chemistry. 2026. DOI: 10.1021/acs.jmedchem.6c01271.

Предметные рубрики MeSH

T-Lymphocytes, RegulatoryAnimalsHumansIkaros Transcription FactorMiceAntineoplastic AgentsDrug DiscoveryNeoplasmsTumor MicroenvironmentCell Line, Tumor
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