In 2015, there were over 75 thousand new leukemia patients in China with a death rate of around 70%, and also over 88 thousand new lymphoma patients with a death rate of around 59%.

Deregulation of PI3Kδ, such as over-expression, has been found in B-cell malignances such as chronic lymphatic leukemia (CLL), indolent non-Hodgkin lymphoma and acute myeloid leukemia (AML). Constitutive activation of B-cell receptor (BCR) or over-expressed growth factors in bone marrow and lymph nodes may activate PI3Kδ-mediated signaling pathway, which will lead to aberrant tumorigenic cell proliferation.

The first FDA-approved PI3Kδ selective inhibitor, CAL-101 (Idelalisib), and its successful clinical application towards CLL and indolent NHL, have validated PI3Kδ as a drug discovery target. However, both preclinical and clinical tests have shown that inhibition of PI3Kδ alone only exerted limited direct cytotoxicity against the transformed cells, but rather inhibited cell survival by interfering with the microenvironment.

Recently, Dr. LIU Qingsong's research group from High Magnetic Field Laboratory of the Chinese Academy of Sciences discovered a high potent and selective PI3Kδ/VPS34 dual inhibitor- PI3KD/V-IN-01 for B cell related malignancies.

Inhibition of the PI3K/AKT/mTOR signaling pathway is known for inducing autophagy, which could provide a pro-survival mechanism for the cancer cells to escape apoptosis. In addition, there is evidence that treatment of CLL cells with CAL-101 induces autophagy. Therefore, simultaneous inhibition of PI3Kδ and autophagy might enhance the clinical efficacy of PI3Kδ inhibitors.

Using a high throughput screening technology, the team discovered a dual inhibitor PI3KD/V-IN-01 targeting not only PI3Kδ, but also VPS34, which plays critical role in autophagy.

In the anti-proliferation assays, PI3KD/V-IN-01 displayed an IC₅₀ of 6 nM against PI3Kδ and 19 nM against VPS34. In contrast, the drug showed little activity against other PI3Ks. Further characterization of the selectivity profile with the DiscoveRx’s KinomeScan^TM platform showed that PI3KD/V-IN-01 (1 μM) was highly selective and did not potently bind to any of the other protein kinases.

PI3KD/V-IN-01 exhibits more potent anti-proliferation activity than the selective PI3Kδ inhibitor, CAL-101, and selective Vps34 inhibitor, Vps34-IN-1, against most of the cell lines tested, especially several FLT3-ITD-positive cell lines. PI3KD/V-IN-01 suppresses the PI3Kδ-mediated signaling pathway, interferes with autophagy, and arrests cell cycle progression in AML and CLL cell lines. PI3KD/V-IN-01 inhibited growth of CLL patient primary cells and AML primagraft cells and also displayed anti-tumor activity in an MV4-11 inoculated xenograft mouse model.

This work was published in the journal Oncotarget titled Simultaneous inhibition of Vps34 kinase would enhance PI3Kδ inhibitor cytotoxicity in the B-cell malignancies.

This work is supported by the grant of “Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014-2016)”, “Thousand Talents Program” and “Hundred Talents Program” of Chinese Academy of Sciences, and the CAS/SAFEA international partnership program for creative research teams. The protection of both China patent for invention and international PCT patent for this achievement has been applied.

 

PI3KD/V-IN-01 exhibits anti-proliferation activity against Chronic Lymphatic Leukemia (CLL) and Acute Myeloid Leukemia. (Image by Ellen Weisberg and QI Ziping)