Molecule

Description

R547 is a potent and selective CDK inhibitor with K_i and IC50 of 1-3 nM and 80 nM respectively.

Targets

IC₅₀

In Vitro

R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1–3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μm.="" r547="" reduces="" phosphorylation="" of="" the="" cellular="" retinoblastoma="" protein="" at="" specific="" cdk="" phosphorylation="" sites="" at="" the="" same="" concentrations="" that="" induced="" cell="" cycle="" arrest,="" suggesting="" a="" potential="" pharmaco="" dynamics="" marker="" for="" clinical="" use.="" r547="" inhibits="" the="" proliferation="" of="" tumor="" cell="" lines="" and="" is="" active="" in="" all="" 19="" cell="" lines="" tested="" irrespective="" of="" tissue="" of="" origin,="" multidrug="" resistance="" (mdr),="" p53,="" or="" retinoblastoma="" status.="">^[1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). ^[2]

In Vivo

R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01).="" r547="" administered="" orally="" at="" dose="" of="" 40="" mg/kg="" daily="" in="" colon,="" lung,="" breast,="" prostate,="" and="" melanoma="" human="" tumor="" xenograft="" models="" shows="" significant="" tgi="" (79–99%).="" r547="" is="" equally="" efficacious="" (tgi,="" 61–95%)="" when="" dosed="" with="" 40="" mg/kg="" i.v.="" once="" weekly.="" these="" doses="" of="" r547="" are="" not="" toxic="" and="" did="" not="" result="" in="" body="" weight="" loss.="" r547="" does="" not="" show="" signs="" of="" overt="" toxicity="" during="" the="" course="" of="" the="" 3-week="" study="" and="" any="" gross="" pathology="" at="" necropsies="" done="" at="" the="" end="" of="" the="" studies.="">^[1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. ^[2]

Clinical Trials

R547 is currently in Phase I clinical trial for the treatment of cancer.

Features