Saturday, November 7, 2015

Drugs in Clinical Pipeline: Acalisib

Acalisib [(S)-2-(1-((7H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one] is a potent, selective nanomolar inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA phosphoinositide-3 kinases (PI3K). 

Acalisib was more selective for PI3Kδ relative to other PI3K class I enzymes (IC50: PI3Kδ = 12.7 nM; PI3Kα = 5441 nM; PI3Kβ = 3377 nM and PI3Kγ = 1389 nM). Acalisib was also 1000-fold more selective against PI3Kδ than against related kinases, such as CIIβ, hVPS34, DNAPK, and mammalian target of rapamycin (mTOR) [1].

Acalisib was also assayed for its potential binding interaction with kinases by screening a comprehensive panel of 393 kinases, including mutants, in the Ambit KINOMEscan. No binding outside of PI3K was observed at 10 µM Acalisib, further demonstrating a high degree of selectivity. Acalisib was considered active if less than 35% of binding to immobilized probes remained compared to DMSO control. Various PI3K isoforms have %control binding values in the 0.25-14 range. The next kinase target was PIP5K2B with a value of 49% [1].

Acalisib is under investigation for the treatment of lymphoid malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [2].

The activity of Acalisib is as follows:

IC50 (PI3Kδ enzyme assay) = 12.7 nM
IC50 (PI3Kα enzyme assay) = 5441 nM
IC50 (PI3Kβ enzyme assay) = 3377 nM
IC50 (PI3Kγ enzyme assay) = 1389 nM
IC50 (DNA-PK enzyme assay) = 18.7 uM
IC50 (mTOR enzyme assay) = greater than 1 uM
IC50 (CIIβ enzyme assay) = greater than 1 uM
IC50 (hVPS34 enzyme assay) = 12.6 uM

Common Name: Acalisib
Synonyms: GS-9820; GS9820; GS 9820; CAL-120; CAL 120; CAL120
IUPAC Name: (S)-2-(1-((7H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one
CAS Number: 870281-34-8
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; PI3Kdelta Inhibitor
Indication: Various Cancers; Anti-Tumor Agents; Autoimmune Disease Treatment
Development Stage: Phase I

Company: Gilead Sciences

1. Shugg, R. P.; et. al. Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption. J Biol Chem 2013, 288(49), 35346-35357.
2. Jun, S.; et. al. Interim Analysis Of A Phase 1B Study Evaluating The Safety Of GS-9820, A Second-Generation PI3Kd-Inhibitor, In Relapsed/Refractory Lymphoid Malignancies. 13th International Conference on Malignant Lymphoma. 17-20 June 2015 Lugano, Switzerland.