Oss, April, 8th, 2016 – At the AACR 2016 conference, to be held in New Orleans next week, Jos de Man, Senior Investigator Chemistry at NTRC, will present on the unique binding mode of NTRC’s TTK kinase inhibitor clinical candidate NTRC 0066-0. The oral presentation is scheduled on Monday, April 18th, in the Minisymposium ‘Hitting the Target Harder’ (3 – 5 p.m. in Theater A of the Morial Convention Center).
The protein kinase TTK is a component of the spindle assembly checkpoint, a protein machinery that regulates correct segregation of chromosomes over daughter cells during cell division. Inhibition of TTK results in chromosome missegregation and apoptosis of tumour cells. NTRC has developed a series of highly selective inhibitors of TTK enzyme activity that potently inhibit proliferation of human cancer cells and tumour growth in mouse models.[1,2] At the AACR, the X-ray protein crystal structure of TTK in complex with NTRC 0066-0 and other TTK inhibitors will be presented. A unique kinase – inhibitor binding mode was observed that was used to develop TTK inhibitors with further increased target residence time by medicinal chemistry and NTRC’s Biacore platform ResidenceTimer™. Increased target residence time correlated with increased activity of TTK inhibitors in cancer cell line proliferation assays.
NTRC will also present a poster on OncolinesProfiler™, the comparative analysis of drug candidates in cancer cell line proliferation assays. The inhibition profiles of 120 anti-cancer agents were compared, revealing 43 therapeutic clusters, many of them taken by novel therapies that were never part of any comparative profiling. It is shown that the biochemical target of an inhibitor predicts its clustering, and that empirical cell line responses correspond to well-known cancer hallmarks. Different subclasses of PI3K/mTOR, Aurora and EZH2 inhibitors were identified that relate to different mechanisms of activity or different genetic targeting. Also data on the reproducibility of NTRC’s Oncolines™ profiling over a period of more than three years will be presented.
Oral presentation on TTK and ResidenceTimer™:
Title: “The unique binding mode of NTRC 0066-0, a novel inhibitor of the spindle assembly checkpoint kinase TTK (Mps1), leads to long target residence time and potent antitumor activity”
Abstract number: 2646
Presenting author: Jos de Man
Date: April 18th (Monday)
Time: 4.20 p.m. – 4.35 p.m.
Location: Theater A
Poster presentation on OncolinesProfiler™:
Title: “Comparative cancer cell line profiling differentiates the mechanism of action of different PI3K/mTOR, Aurora kinase and EZH2 inhibitors”
Abstract number: 4635
Presenting author: Dr. Joost Uitdehaag
Date: April 20th (Wednesday)
Time: 8 a.m. – 12 p.m.
Location: Halls G-J, Poster Section 14
Literature references:  de Man et al. (2015) WO 2015/155042 A1;  Maia et al. (2015) Annals of Oncology 26, 2180-2192
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, SynergyFinder™ and OncolinesProfiler™), target residence time measurements for protein kinases (ResidenceTimer™), and developing new enabling technologies, such as NFK GreenScreen™. In addition, NTRC develops own novel targeted therapies based on small molecules, such as selective inhibitors of TTK (Mps1) protein kinase for chromosomal unstable tumours and inhibitors of the tryptophan metabolizing enzymes IDO1 and TDO for cancer immunotherapy. For more information please visit www.ntrc.nl or contact [email protected]