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PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ 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 PI3Kδ 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 expression 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 during 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 sensitized 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 suppressive 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, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

Target engagement kinase tree

Table summarizing the IC50 values derived from previous published experiments performed with IOA-244

PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ 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 PI3Kδ 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 expression 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 during 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 sensitized 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 suppressive 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, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

Correlation analysis of PI3Kd levels and the response to IOA-244 and Idelalisib

Phosphoinositide 3-kinase delta (PI3Kd) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kd inhibition in solid tumors has recently emerged as a potential novel anti-cancer therapy through the modulation of T cell responses and direct anti-tumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3Kd 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 expression levels of PIK3CD, suggesting cancer cell-intrinsic effects of IOA-244. Importantly, IOA-244 inhibits Treg proliferation while having limited anti-proliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 during 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 LLC lung cancer models, IOA-244 sensitized 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 NK cells, while decreasing suppressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical Phase Ib/II investigation in solid and hematological tumors.

Table showing values of microsomal stability of IOA-244

Background Rhinovirus (RV) is a major respiratory virus that poses a threat to immunocompromised people and those with underlying disease. However, there are no approved therapies. Moreover, RV infection cannot be prevented by a vaccine because there are over 100 serotypes. Here we report the pharmacological profile of a novel small-molecule host-targeted antiviral (HTA), KRP-A218 (A218). A highly potent and selective inhibitor of phosphatidylinositol 4 kinase beta (PI4KB), a key host factor of RV replication, A218 is undergoing clinical study. Methods in vitro antiviral activities of A218 and Vapendavir (Vap), a virus-targeted antiviral, were examined by inhibition of CPE, viral load, or replication. in vivo antiviral activity and pathological analysis of A218 were examined in coxsackievirus B3 (CVB3; belong to the genus enterovirus as with RV)-infected mice as a surrogate model of RV infection as CVB3, unlike RV, replicates very well in both mouse and human tissue. Daily oral dosing of A218 (1-10 mg/kg) was started 2 days post intraperitoneal infection with CVB3. Tissue viral load, pancreas pathological change at 4 days post infection, and survival rate up to 14 days were evaluated. PI4KB heterozygous kinase-dead mice (PI4KB KD) were established by a CRISPR-Cas9 system. Viral load and survival rate following viral infection were evaluated in these mice. Results A218 showed broad antiviral activity for RV and enteroviruses (Table) and has a higher barrier to drug resistance than Vap. These results are consistent with expectations for HTAs. Repeated dosing of A218 starting 2 days post infection decreased viral load and improved acute pancreatitis, accompanied by decrease of inflammatory and pancreatitis markers in plasma. Moreover, therapeutic dosing of A218 improved survival rate in a CVB3-infected lethal mouse model (Figure). These results show the first evidence that a PI4KB inhibitor has potent therapeutic efficacy in a severe viral infection model. Similar effects were observed in PI4KB KD, supporting the on-target effect of A218. Table. Antiviral activity of A218 and Vap against RV/EV infection Figure. Therapeutic effect of A218 on survival rate in CVB3-infected mice Conclusion A218 is a promising therapeutic agent for improving the exacerbation of pathological conditions caused by RV infection. Nonclinical package including GLP-Tox also supports the ongoing first-in-human study of A218. Disclosures Toshiyuki Matsui, MPharm, Kyorin pharmaceutical Co., LTD (Employee) Motomichi Fujita, PhD, Kyorin Pharmaceutical Co., Ltd. (Employee) Yuji Ishibashi, PhD, Kyorin Pharmaceutical co., ltd. (Employee) Tyzoon Nomanbhoy, PhD, ActivX Biosciences (Other Financial or Material Support, Full time employee of ActivX, a wholly owned subsidiary of Kyorin Pharmaceuticals) Jonathan S. Rosenblum, PhD, ActivX Biosciences (Employee) Michiaki Nagasawa, PhD, Kyorin Pharmaceutical Co., Ltd (Employee)