Phosphatidylinositol 3-kinases (PI3Ks) belong to a family of lipid signaling kinases that phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2), giving rise to phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. The delta isoform of PI3K (PI3Kδ) plays an essential role in both B cell development and function, and has now been validated as a therapeutic target in CLL and indolent NHL upon the approval of idelalisib, a selective PI3Kδ inhibitor. However, despite the demonstrated activity of PI3Kδ inhibitors in several subtypes of B cell malignancies, the effectiveness of the approach as a single agent for the treatment of DLBCL, the largest subtype of NHL, has not been demonstrated. We hypothesized that an optimal treatment strategy in this histology would require combined inhibition of PI3Kδ with additional agents that target B cells through distinct signaling pathways.

INCB050465 is a novel, small molecule inhibitor of PI3Kδ. In biochemical assays, it potently inhibits PI3Kδ (IC50 = 1 nM at 1 mM ATP) with approximately 20,000-fold selectivity for PI3Kα, PI3Kβ, PI3Kγ and 57 other kinases. In various PI3Kδ functional assays, including B cell proliferation induced by activation of BCR, BAFF-R, IL-4R, CD40 and TLRs as well as T cell differentiation assays, INCB050465 demonstrates potent activity with IC50 values ranging from 0.2 to 2 nM. In addition, INCB050465 blocks the proliferation of several DLBCL and MCL cell lines in vitro (EC50 < 10 nM) and can slow tumor growth in the Pfeiffer model of DLBCL in vivo. In cells, INCB050465 blocks constitutive PI3Kδ signaling, including phosphorylation of Akt and FOXO3a, with potencies similar to those for inhibiting proliferation. More importantly, the ability of INCB050465 to inhibit DLBCL cell proliferation in vitro can be further potentiated by inhibition of PIM (Proviral Integration sites for Moloney virus) protein kinases, which were also found to be important for B cell development and to phosphorylate substrates which overlap with those of the PI3K pathway. The combined inhibition of PI3Kδ by INCB050465 with the potent and selective PIM protein kinase inhibitor, INCB053914, results in profound tumor regression in the Pfeiffer cell model of DLBCL. Taken together, these results provide evidence for cross-talk between the PIM and PI3Kδ pathways, and support a mechanistic rationale for the clinical evaluation of combined PIM and PI3Kd inhibition in B cell malignancies, including DLBCL.

Citation Format: Niu Shin, Holly Koblish, Maryanne Covington, Yanlong Li, Kathy Wang, Qian Wang, Patricia Feldman, Leslie Hall, Sybil O'Connor, Xin He, Kamna Katiyar, Yu Li, Eddy W. Yue, Thomas P. Maduskuie, Brent Douty, Song Mei, Yun-Long Li, Chu-Biao Xue, Andrew Combs, Wenqing Yao, Sharon Diamond-Fosbenner, Swamy Yeleswaram, Robert Newton, Kris Vaddi, Reid Huber, Peggy Scherle. INCB050465, a novel PI3Kδ inhibitor, synergizes with PIM protein kinase inhibition to cause tumor regression in a model of DLBCL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2671. doi:10.1158/1538-7445.AM2015-2671