TY - JOUR T1 - Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase <em>δ</em> Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 211 LP - 222 DO - 10.1124/jpet.120.265538 VL - 374 IS - 1 AU - Niu Shin AU - Matthew Stubbs AU - Holly Koblish AU - Eddy W. Yue AU - Maxim Soloviev AU - Brent Douty AU - Kathy He Wang AU - Qian Wang AU - Mingming Gao AU - Patricia Feldman AU - Gengjie Yang AU - Leslie Hall AU - Michael Hansbury AU - Sybil O’Connor AU - Lynn Leffet AU - Robert Collins AU - Kamna Katiyar AU - Xin He AU - Paul Waeltz AU - Paul Collier AU - Jin Lu AU - Yun-Long Li AU - Yanlong Li AU - Phillip C.C. Liu AU - Timothy Burn AU - Maryanne Covington AU - Sharon Diamond AU - Dana Shuey AU - Alan Roberts AU - Swamy Yeleswaram AU - Greg Hollis AU - Brian Metcalf AU - Wenqing Yao AU - Reid Huber AU - Andrew Combs AU - Robert Newton AU - Peggy Scherle Y1 - 2020/07/01 UR - http://jpet.aspetjournals.org/content/374/1/211.abstract N2 - The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti–B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling–mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861).SIGNIFICANCE STATEMENT The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds. ER -