Description

In Vivo Proof-of-Principle

A lead compound has been identified, which is a potent orally bioavailable inhibitor of FLT3 (IC50 35nM), Aurora-A (IC50 15nM) and Aurora-B (IC50 100nM) with minimal activity against a panel of over 100 kinases. The lead compound demonstrates potent cellular activity and robust oral in vivo efficacy; it causes potent dose-dependent growth inhibition of MOLM-13 (AML) xenografts on oral delivery with concomitant biomarker modulation consistent with dual FLT3 and Aurora inhibition in vivo. Moreover, the lead compound causes growth inhibition of MV4-11 (also AML) xenografts and overcomes resistance to selective FLT3 inhibition in MOLM13-MLN518- resistant human tumour xenografts. The lead compound also inhibits tumour growth in transgenic and primary transplant MYCN-driven neuroblastoma models and HCT116 colon tumour xenografts. A patent has been filed around the lead series; other valuable IP includes established biological assays, cellular and in vivo PD biomarkers. Inhibitors with a selective FLT3 / Aurora-A inhibition profile are also available; these display high selectivity for Aurora-A versus Aurora-B in both biochemical and cellular assays (>480 fold). X-ray co-crystal structures that educate the binding mode and selectivity of this series have been obtained.

CRT is now seeking a commercial partner to further progress the FLT3 / pan-Aurora inhibitor compounds through preclinical development and/or progress the FLT3 / Aurora-A selective compounds to preclinical development candidates. Capacity and expertise to run first-in-man and paediatric clinical trials with PK/PD support could be available through The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Download the PDF of Novel Dual Inhibitors of FLT3 and Aurora Kinases

For more information please contact

Dr Anne Horgan

+44 (0) 20 3469 6300 .(JavaScript must be enabled to view this email address)