IOA-244 is a Non-ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance Check for updates

PI3K delta (PI3K & delta;) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3K & delta; inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3K & delta; inhibitor, for the treatment of solid tumors. We confirm IOA-244's selectivity as tested against a large set of kinases, enzymes, and receptors. IOA-244 inhibits the in vitro growth of lymphoma cells and its activity correlates with the expres-sion levels of PIK3CD, suggesting cancer cell-intrinsic effects of IOA-244. Importantly, IOA-244 inhibits regulatory T cell proliferation while having limited antiproliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 dur-ing activation, favors the differentiation of memory-like, long-lived CD8, known to have increased antitumor capacity. These data highlight immune - modulatory properties that can be exploited in solid tumors. In CT26 colorectal and Lewis lung carcinoma lung cancer models, IOA-244 sensi-tized the tumors to anti-PD-1 (programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. IOA-244 reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and natural killer cells, while decreasing sup-pressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical phase Ib/II investigation in solid and hematologic tumors. Significance: IOA-244 is a first-in-class non-ATP-competitive, PI3K & delta; inhibitor with direct antitumor in vitro activity correlated with PI3K & delta; ex-pression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the ratio-nale for the ongoing trials in patients with solid tumors and hematologic cancers.