Abstract 5169: Identification and optimization of pyridylbenzylamine analog 1 as potent and selective Helios degrader

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Abstract Small molecule approaches that enhance antitumor immunity have the potential to broaden the benefit of cancer immunotherapy as monotherapies or in combination with immune checkpoint inhibitors (ICIs). Indeed, despite the success of ICIs, resistance and limited response in some patients highlight the need for alternative strategies. FOXP3+ regulatory T (Treg) cells within the tumor microenvironment (TME) suppress antitumor immunity and limit the efficacy of ICIs in some tumor types. Transcriptional reprogramming of Treg cells represents a novel and promising therapeutic approach to treat such patients. IKZF2 (Helios), a zinc finger transcription factor selectively expressed in Treg cells, contributes to the transcriptional immunosuppressive phenotype of these cells, including silencing of IL-2 expression. Genetic deletion of IKZF2 in FOXP3+ cells enhances antitumor responses in preclinical models, establishing it as a nonredundant regulator of Treg cell function. Although transcription factors have traditionally been considered “undruggable,” the discovery of cereblon (CRBN)-mediated degradation of zinc finger proteins by immunomodulatory imide drugs (IMiDs™) has enabled targeted protein degradation (TPD) of factors such as IKZF1 (Ikaros) and IKZF3 (Aiolos). We recently disclosed the discovery of a potent and selective IKZF2 degrader, BMS-986449, derived from lenalidomide/pomalidomide scaffolds. Herein, we report SAR optimization studies leading to the identification of a pyridylbenzylamine appended lenalidomide analog (compound 1) with excellent Helios degradation activity and improved selectivity over related neosubstrates (e.g. IKZF1, IKZF3, and CK1α). In addition, 1 also exhibited favorable ADME properties and robust in vivo pharmacodynamic effects in a mouse syngeneic model. Citation Format: Ashok Purandare, Godwin Kumi, Guo Li, Aaron Balog, Emily Cherney, Michael Barnes, Satheesh Nair, Sirish K. Lakharaju, Xin Li, Robin Moore, Petia Shipkova, Silvi Chacko, Cullen Cavallaro, Ling Li, Kimberly Foster, Keith DiPetrillo, Gerry Everlof, Kevin Stefanski, Steven Levine, Lihong Shi, Jinqi Liu, Helen Pham, Ari Salinger, Ashok Dongre, Shailesh Dudhgaonkar, Debarati Mazumder, Anuradha Gupta, Vetrichelvan Muthalagu, Madhusudhan Ravindran, Yan Chen, Weifang Shan, Suresh Babu Viswa Krishna Penmetsa, Carolyn Weigelt, Robert Borzilleri, Louis Lombardo, Gregory Vite, John Hunt. Identification and optimization of pyridylbenzylamine analog 1 as potent and selective Helios degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5169.

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