Abstract
PI3Kδ is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate anti-proliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.
Highlights
Mammalian PI3K lipid kinases are composed of three classes – I, II, and III, which are involved in multiple cellular functions, including signaling transduction, cell proliferation, differentiation, etc. [1] Constitutive activation or overexpressions of PI3Ks have been implicated in variety of human cancers [2]
PI3KD-IN-015 did not inhibit PI4KA (IC50 over 10mM) and exhibited 34-fold selectivity against PI4KB (IC50: 172 nM). (Figure 1B) Its selectivity profile was better than pan-PI3K inhibitor GDC-0941 but less than well-established PI3Kδ inhibitor CAL-101 in general. (Table 1) it displayed better selectivity profile than CAL-101 between PI3Kδ and PI3Kγ
In order to further confirm the selectivity of PI3KD-IN-015 among the class I PI3Ks, we looked at the cellular effects of PI3K-IN-015 on PI3K signaling pathway
Summary
Mammalian PI3K lipid kinases are composed of three classes – I, II, and III, which are involved in multiple cellular functions, including signaling transduction, cell proliferation, differentiation, etc. [1] Constitutive activation or overexpressions of PI3Ks have been implicated in variety of human cancers [2]. Mammalian PI3K lipid kinases are composed of three classes – I, II, and III, which are involved in multiple cellular functions, including signaling transduction, cell proliferation, differentiation, etc. While PI3Ka and b are ubiquitously expressed in all of the mammalian tissues, PI3Kδ and g are predominately expressed in the lymphocytes, and has been proved to be essential for B-cell survival, proliferation, and migration [4, 5].Among these, PI3Kδ is over-expressed/ aberrantly activated in a variety of B-cell malignances such as CLL and AML [6, 7]. We report the discovery of another potent and selective PI3Kδ inhibitor, PI3KD-IN-015, which exhibits potent and selective inhibitory effects against the PI3Kδ-mediated signaling pathway and the proliferation of both established cancer cell lines and primary CLL and AML patient cells
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