CAL-101

Absorption

Following oral administration, the median Tmax was observed at 1.5 hours.

Description

Idelalisib (CAS 870281-82-6) is a potent (IC50 = 2.5nM) and selective (IC50’s: PI3Ka = 820nM, PI3Kb = 565nM, PI3Kg = 89nM) PI3Kd inhibitor.1,2 Useful clinical agent for the treatment of various blood cancers. Idelalisib attenuates regulatory T cells (Treg) but not conventional T cells (Tconv) resulting in a significant increase in tumor-infiltrating antigen-specific CD8 T cells in a murine lung cancer model.3 Conversely, systemic PI3Kd inactivation antagonized anti-CTLA-4 and anti-PD-L1 treatment.4 Others have found that Idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity in human lymphoma cells.5

The Uses of CAL-101

CAL-101 is a PI3K/mTOR pathway inhibitor used in the treatment of myeloid leukemia through sensitizing the cells to combatting drugs. Potent PI3K-p110-delta inhibitor.

Indications

Idelalisib is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies.

Background

Idelalisib is a phosphoinositide 3-kinase inhibitor indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies. More specifically, idelalisib targets P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase, also known as PI-3K. The PI-3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells) and is important for the function of T cells, B cell, mast cells and neutrophils. By inhibiting this enzyme, idelalisib induces apoptosis of malignant cells and inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and C-X-C chemokine receptors type 5 and type 4 signalling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to result in inhibition of chemotaxis and adhesion, and reduced cell viability.

What are the applications of Application

CAL-101 is a potent PI3K p110δ inhibitor

Definition

ChEBI: A member of the class of quinazolines that is 5-fluoro-3-phenylquinazolin-4-one in which the hydrogen at position 2 is replaced by a (1S)-1-(3H-purin-6-ylamino)propyl group. used for for the treatment of refractory indol nt non-Hodgkin's lymphoma and relapsed chronic lymphocytic leukemia.

Metabolism

Idelalisib is metabolized by aldehyde oxidase and CYP3A to its major metabolite GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a minor extent by UGT1A4.

storage

Store at -20°C

References

1) Herman?et al. (2010), Phosphatidylinositol 2-kinase-d inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals; Blood?116 2078 2) Lannutti?et al. (2011), CAL-101, a p110d selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability; Blood 117 591 3) Ahmad?et al. (2017), Differential PI3Kd Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy; Cancer Res. 77 1892 4) Lim?et al. (2018), Phosphoinositide 3-kinase d inhibition promotes antitumor responses but antagonizes checkpoint inhibitors; JCI Insight 3 e120626 5) Palazzo?et al.?(2018),?The PI3Kd-Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function Mediated by Rituximab or Obinutuzumab and Significantly Augment B Cell Depletion In Vivo; J.Immunol. 200 2304