Phosphoinositide 3-kinases (PI3Ks) can catalyze the synthesis of the phosphatidylinositol (PI) second messengers, including PI(3)P (PIP), PI(3,4)P2 (PIP2), and PI(3,4,5)P3 (PIP3). The PI3K lipid kinase family contains three classes based on sequence homology. Class, I PI3Ks are further divided into class IA (PI3Kα, PI3Kβ, and PI3Kδ) and class IB (PI3Kγ).

PI3Kα is the predominant catalytic isoform and plays an important role in glucose homeostasis regulation and vasculogenesis. Whereas PI3Kβ plays a secondary role in insulin signaling.

Additionally, the PI3Kδ and PI3Kγ isoforms are primarily expressed in leukocytes and exert important roles in immune response and inflammation.

In this article, we will introduce a highly selective PI3Kα inhibitor, PF-06843195.

The Ki values of PF-06843195 for PI3Kα and PI3Kδ in biochemical kinase assay are less than 0.018 nM and 0.28 nM, respectively. Consistent with its high enzyme selectivity, PF-06843195 also exhibits high cellular selectivity. To evaluate the isoform-specific potency of PF-06843195 cell-based system. Rat1 fibroblasts express an N-terminally myristoylated form of each PI3K class IA isoform.PF-06843195 is against rat1 PI3Kα, PI3Kβ, and PI3Kδ with IC50 values of 18 nM, 360 nM, and 160 nM, respectively.

Besides, it also exhibits high cellular selectivity (83-fold) over mTOR, the IC50 is 1500 nM. PF-06843195 inhibits the breast cancer cell lines MCF7 and T47D proliferation with IC50s of 62 nM and 32 nM, respectively. Additionally, PF-06843195 inhibits pAKT (T308) in MCF7 and T47D cells with IC50s of 7.8 nM and 8.7 nM, respectively.

In a pharmacokinetic analysis with Male Wistar Han Rats. 10 mg/kg PF-06843195 exhibits an oral bioavailability of 25 %. Following an intravenous administration of 2 mg/kg, PF-06843195 exhibits a moderate half-life (rat 3.6 h) due to high plasma clearance (30 mL/min/kg) combined with large volumes of distribution (3.0 L/kg).

In conclusion, as a selective PI3Kα inhibitor, PF-06843195 possesses anti-cancer activities. PF-06843195 has great suppression of the PI3K/mTOR signaling pathway and durable antitumor efficacy. This compound has the potential for cancer research.

Hengmiao Cheng, et al. J Med Chem. 2021 Jan 14;64(1):644-661.