Uses
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.
Definition
ChEBI: PP121 is a pyrazolopyrimidine that is 1H-pyrazolo[3,4-d]pyrimidine which is substituted by a cyclopentyl, 1H-pyrrolo[2,3-b]pyridin-5-yl, and amino groups at positions 1, 3 and 4, respectively. It is a dual inhibitor of tyrosine and phosphoinositide kinases and exhibits anti-cancer properties. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, a tyrosine kinase inhibitor and an antineoplastic agent. It is a pyrazolopyrimidine, a pyrrolopyridine, a member of cyclopentanes and an aromatic amine.
General Description
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, SrcT338I, 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.
Biological Activity
pp121 is a dual inhibitor of tyrosine and phosphoinositide kinases [1].pp121 is found to inhibit both tyrosine kinases and pi3-ks but not serine-threonine kinases. it potently inhibits p110α, p110β, p110γ, p110δ, dna-pk and mtor with ic50 values of 52nm, 1.4μm, 1.1μm, 150nm, 60nm and 10nm, respectively. for the tyrosine kinases, pp121 shows inhibition with ic50 values of 21nm, 4nm, 10nm,55nm, 550nm, 220nm and <1nm for ab1, hck, src, vegfr2, egfr, ephb4 and pdgfr, respectively [1].in cells, pp121 can reverse v-src mediated cellular transformation and restore actin stress fiber staining. pp121 also potently inhibits the mutant ret kinase with ic50 value less than 1nm in thyroid tumors34. furthermore, pp121 is found to evade drug resistance through redundantly targeting bcr-abl mediated cell survival and pi3-k/mtor mediated cell proliferation [1].
Biochem/physiol Actions
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.
References
[1] apsel b, blair j a, gonzalez b, et al. targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. nature chemical biology, 2008, 4(11): 691-699.
