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Abstract Tumor-associated macrophages are an integral part of the tumor microenvironment. They play a crucial role in cancer initiation and progression by orchestrating tumor proliferation, angiogenesis, extracellular matrix remodeling, metastasis, immunosuppression, and resistance to checkpoint blockade immunotherapy and chemotherapy (Gao J, 2022). On the other hand, when properly stimulated, macrophages can effectively interact with the innate and adaptive immune systems arms, promoting cancer cell phagocytosis and tumor destruction by T cell-mediated cytotoxicity (Mantovani A, 2022). PI3Kγ has a unique pattern of expression and biological function, and it has been investigated for a long time as a therapeutic target for different disorders, including cancer. Inhibition of PI3Kγ reprograms M2 macrophages into M1 cells in the tumor microenvironment which translates into the expansion of activated T cells by relieving macrophage suppression. Recent clinical data indicates the compelling role of PI3Ky in combination with PDL1 in anti-tumor activity, irrespective of PDL1 status (Hamilton E, 2021). PI3Ky selectivity has been difficult to achieve due to the high sequence homology across the class 1 PI3K isoforms (Drew SL, 2020). Macrocyclization of small molecules with a linear structure strongly reduces their conformational flexibility and alters a variety of their physicochemical and biological characteristics. The unexpected selectivity these compounds can exhibit, even amongst closely similar target molecules, is explained by the conformationally limited structure (Ma J, 2022). Here, we describe the discovery of a potent and selective, ATP-competitive inhibitor of PI3Kγ. OPM-116, macrocyclic compound display 300-fold selectivity for PI3Kγ over the other class I isoforms. Its selectivity in biochemical and cellular assays as well as in human PBMC assays is presented. In vitro, OPM-116 can inhibit the IL-4-induced polarization of M2 macrophages. Pharmacodynamic analysis performed in animals that received oral compound administration confirmed the absolute selectivity and good PK profiles of the drug. OPM-116 is a highly selective, PI3Kγ inhibitor that displays high potency and specificity and represents a promising step toward the identification of a clinical candidate. Drew S. L. , et al. Discovery of potent and selective PI3Kγ inhibitors. J. Med. Chem. 2020. Ma J. , et al. Development of small macrocyclic kinase inhibitors. Futur. Med. Chem. 2022. Gao J. , et al. Shaping polarization of tumor-associated macrophages in cancer immunotherapy. Front. Immunol. 2022. Mantovani A, et al. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discovery. 2022. Hamilton E, et al. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib, atezolizumab, and nab-paclitaxel as first-line therapy for locally advanced or metastatic TNBC. AACR, Cancer Res 2021. Citation Format: Kenji Shoji, Petra Blom, Maria Eugenia Riveiro, Jan Hoflack. OPM-116, a highly potent and specific PI3Kγ inhibitor to enhance antitumor immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1957.
Shoji et al. (Fri,) studied this question.