INCB040093 Is a Novel PI3KδInhibitor for the Treatment of B Cell Lymphoid Malignancies

Autor: Sharon Diamond, Kamna Katiyar, Qian Wang, Andrew P. Combs, Holly Koblish, Gengjie Yang, Jordan S. Fridman, Maryanne B. Covington, Gregory Hollis, Yanlong Li, Jun Li, Swamy Yeleswaram, Xin He, Reid Huber, Yun-Long Li, Lynn Leffet, Mark Rupar, Kathy Wang, Dana Shuey, Wenqing Yao, Leslie Hall, Maxim Soloviev, Kevin Bowman, Robert C. Newton, Mike Liu, Margaret F. Favata, Peggy Scherle, Timothy Burn, Kris Vaddi, Beth Rumberger, Song Mei, Niu Shin
Rok vydání: 2017
Předmět:
Zdroj: Journal of Pharmacology and Experimental Therapeutics. 364:120-130
ISSN: 1521-0103
0022-3565
DOI: 10.1124/jpet.117.244947
Popis: Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1β (MIP-1beta) and tumor necrosis factor-β (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.
Databáze: OpenAIRE
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