Idelalisib (CAL-101)

CLL B cells or healthy volunteer T cells or NK cells

Currently under Phase II clinical trial in patients with relapsed or refractory hodgkin lymphoma.

CAL-101 is a selective PI3K class I inhibitor of p110delta with IC50 of 2.5 nM.

CAL-101 is not sensitive to other PI3K class I subunits including p110alpha, p110beta, and p110gamma. CAL-101 specifically blocks FcepsilonR1 p110delta-mediated CD63 expression with an EC50 of 8 nM in primary basophil. CAL-101 exhibits greater activity in B-cell acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia (CLL) cells compared with acute myeloid leukemia (AML) and myeloproliferative neoplasm (MPN) cells. CAL-101 produces the reduction in pAktS473, pAktT308, and the downstream target S6 in SU-DHL-5, KARPAS-422 and CCRF-SB cells with EC50 of 0.1 to 1.0 uM. [1] CAL-101 induces selective cytotoxicity in CLL cells independent of IgVH mutational status or interphase cytogenetics, primarily through a caspase-dependent mechanism. CAL-101 induces cytotoxicity preferentially to CLL cells compared with normal B cells, without producing cytotoxicity in other hematopoietic cells, compared to LY294002. CAL-101 lacks direct cytotoxic potential to T cells and nature killer (NK) cells. CAL-101 can inhibit production of inflammatory cytokines, such as IL-6, IL-10, TNF-alpha, and IFN-gamma, and activation-induced cytokines, such as CD40L. CAL-101 also antagonizes CD40L-mediated CLL cell survival. [2] CAL-101 induces an accumulation of cells in G1 and a decrease in the S-phase population in L1236 and L591 cells, which indicates CAL-101 as a novel strategy for the treatment of hodgkin lymphoma (HL). [3]

[2], PI3K assay, PI3K assay is preformed on whole-cell lysates from CLL or normal B cells. A PI3K ELISA assay is performed. Briefly, whole-cell extracts are added to a mixture of PI(4, 5)P2 substrate and reaction buffer containing adenosine triphosphate (ATP) and allowed to incubate at room temperature. The reaction is stopped by adding PI(3, 4, 5)P3 detector mixed with EDTA (ethylenediaminetetraacetic acid) and allowed to incubate at room temperature for 1 hour. After this time, the mixture is transferred from each well to a PI3K ELISA plate and allowed to incubate 1 hour. Plates are washed and then incubated with secondary detector for 30 minutes. Plates are washed again, and 3, 3 , 5, 5 -tetramethylbenzidine solution is added for 5 minutes at which time H2SO4 is added to stop all reactions. Plates are read at 450 nm on a Labsystems 96-well plate reader.

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, , Dr. Zhang, of Tianjin Medical University, CAL-101 (GS-1101)purchased from Selleck, After starved in serum-free medium for 24 h, A549 cells incubated with the indicated concentrations of CAL-101 for 3 h, followed by 20-minute stimolation of 100ng/ml EGF.

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO