1-Cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

PP-121 is a multi-target inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, respectively, and also inhibits DNA-PK with IC50 of 60 nM.

A cell-permeable pyrazolopyrimidine compound that effectively targets the ATP pocket of both protein tyrosine kinases (IC₅₀<0.26 M against Abl, EGFR, EphB4, Hck, PDGFR, RET, Src, Src^T338I, and VEGFR2) and PI 3-K family kinases (IC₅₀<1.4 M against p110α/ β/ δ/ γ, mTOR, and DNA-PK). PP121 is less effective against ser/thr kinases and exhibits significant inhibition of only 14 ser/thr kinases (≥70% inhibition with 1 M inhibitor and 10 M ATP) in a 219 kinase panel screening. Individually targeting Ret by sorafenib (IC₅₀ = 780 nM) or PI 3-K/mTOR pathway by PI-103 (IC₅₀ = 800 nM) is shown to be less effective than PP121 treatment (IC₅₀ = 50 nM) in inhibiting the proliferation of Ret C634W-expressing TT thyroid carcinoma cultures.

PP121 is a dual inhibitor of tyrosine and phosphoinositide kinases. PP121 is the first inhibitor active on both Tyrosine kinases and the phosphatidylinositol-3-OH kinase (PI(3)K) family. The inhibitor is not effecting other serine-threonine protein kinases.