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IC50: 2 nM, 142 nM, 65 nM, 1 nM, and 110 nM for p110α, p110β, p110γ, p110δ, and VPS34, respectively.

The constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors through either gene mutation in the p110a catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. PF-4989216 is a selective oral PI3K inhibitor.

In vitro: PF-4989216 inhibited PI3K downstream signaling and led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in small-cell lung cancer (SCLC) harboring PIK3CA mutation. In SCLC with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator-mediated apoptosis nor was there any effect on cell viability or transformation [1].

In vivo: The mouse in vivo results indicate a good correlation between in vitro and in vivo efficacy, and further confirm that PF-4989216 is an effective drug candidate capable of inducing antitumor activity in mice bearing human SCLC tumors with PIK3CA mutation [1].

Clinical trial: Up to now, PF-4989216 is still in the preclinical development stage.

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