Biological Activity
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].
target
| Target | Value |
p110δ
(Cell-free assay) | 1 nM |
p110α
(Cell-free assay) | 2 nM |
< td style="border-bottom: 1px dotted #ccc;padding: 5px;"> p110γ
(Cell-free assay) 65 nM |
IC 50
2 nm, 142 nm, 65 nm, 1 nm, and 110 nm for p110α, p110β, p110γ, p110δ, and vps34, respectively.
References
[1] walls m, baxi sm, mehta pp, liu kk, zhu j, estrella h, li c, zientek m, zong q, smeal t, yin mj. targeting small cell lung cancer harboring pik3ca mutation with a selective oral pi3k inhibitor pf-4989216. clin cancer res. 2014 feb 1;20(3):631-43.
