School of Natural and Environmental Sciences

Event items

Targeting transcription for therapy

Chemistry Seminar Series - Prof Matthew Fuchter, Imperial College London

Date/Time: Thursday 29 November 2018, 14:00 - 15:00

Venue: Room 1.75 Bedson Building

Abstract

Tight control of gene transcription is essential for cellular development and the establishment of cellular identity. Dysregulation of transcriptional programmes is a common mechanism that leads to the development and maintenance of disease, especially cancer.

Thus, molecular mediators of transcriptional processes represent important and exciting targets for new therapies. This talk will summarise some of our recent efforts at progressing transcriptional targets in cancer and malaria. Specifically, the following thematically-linked projects will be presented:

i) The development of inhibitors of cyclin-dependent kinase 7 (CDK7). CDK7 is necessary for transcription, and acts by phosphorylating RNA polymerase II to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor-α. A large team effort at Imperial College took this project from a clinical hypothesis and virtual chemical scaffolds to a clinical drug candidate which is currently undergoing clinical trials in the UK.1 

ii) The histone lysine methyltransferases (HKMT) as new anti-malarial targets. HKMTs are important epigenetic drug targets and are conserved in the Plasmodium parasite which causes human malaria. We have repurposed an established HKMT inhibitor chemotype for usage as an antimalarial.2 Through this, we have discovered compounds with rapid and irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations including against resistant strains, in vivo efficacy, and the unprecedented ability to reactivate dormant liver stages in culture.3 We have also initiated target-ID studies to validate the target(s) that underpin this exciting activity.

iii) The identification of a small molecule that enhances the production of natural killer (NK) cells. NK cells are critical immune effector cells and the adoptive transfer of large numbers of cytolytic NK cells represents a developing cancer immunotherapeutic approach. We have identified a key nuclear receptor inhibitor that massively enhances the production of NK cells and thus represents a potential opportunity of improved cancer immunotherapy via NK cells. 

1. Patel, H.; et. al. Mol. Cancer Ther. 2018, 17, 1156

2. Sundriyal, S.; et al. MedChemComm 20178, 1069 and papers therein.

3. Dembélé, L.; et al. Nature Med. 201420, 307