tcsc0590 Apitolisib

Apitolisib (GDC-0980) is a selective, potent, orally bioavailable Class I PI3 kinase and mTOR kinase (TORC1/2) inhibitor with IC₅₀s of 5 nM/27 nM/7 nM/14 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ, and with a K_i of 17 nM for mTOR.

IC50 & Target: IC50: 5 nM (PI3Kα), 27 nM (PI3Kβ), 7 nM (PI3Kδ), 14 nM (PI3Kγ)

In Vitro: Apitolisib (GDC-0980) is remarkably selective for several other members of the closely related PIKK family kinases: C2alpha IC₅₀=1300 nM; C2beta IC₅₀=7 94 nM; VPS34 IC₅₀=2000 nM; PI4Kalpha >10 μM; PI4Kbeta >10 μM; DNA-PK Kiapp=623 nM, respectively^[1]. A recent study shows that Apitolisib (GDC-0980) reduces cancer cell viability by inhibiting cell-cycle procession and inducing apoptosis with most potency in prostate (IC₅₀ < 200 nM 50%), <500 nM 100%), breast (IC₅₀ <200 nM 37%, <500 nM 78%) and NSCLC lines (IC₅₀ <200 nM 29%, <500 nM 88%) and less potency in pancreatic (IC₅₀ <200 nM 13%, <500 nM 67%) and melanoma cell lines (IC₅₀ <200 nM 0%, <500 nM 33%)^[2].

In Vivo: Apitolisib (GDC-0980) (1 mg/kg, p.o.) demonstrats significant efficacy in mouse xenografts and is currently in phase I clinical trials for cancer. Clearance and PPB are low, and Apitolisib (GDC-0980) shows dose-proportional exposure from 5 mg/kg dosed in PEG to 50 mg/kg dosed in suspension in MCT, a finding attributed partially to the compound’s good solubility^[1]. Apitolisib (GDC-0980) (5 mg/kg, p.o.) results in greater than 50% TGI in 15 of the 20 xenograft models. The difference in tumor response to Apitolisib (GDC-0980) treatment correlates with the duration of knockdown of pAkt/tAkt^[2].