New cancer therapies

Programme stream(s): Cancer discovery / underpinning research , Treatment
Programme session type(s): Recent Advances session

Chair: Caroline Springer, CRUK Manchester Institute, UK
Speaker: Ian Collins, The Institute of Cancer Research, UK
Speaker: John Bell, University of Ottawa, Canada
Speaker: Allan Jordan, CRUK Manchester Institute, UK

11:00-12:30

Room: M1

This session will cover several aspects of biological and small molecule cancer drug discovery, from target validation to preclinical development. Understand how the drug discovery process starts and progresses towards the clinic. The aim is to become familiar with different strategies to target cancer.

Targeting the DNA Damage Response with a Selective CHK1 Inhibitor
Speaker: Ian Collins
Affiliation: The Institute of Cancer Research

Abstract:

Genome instability is a hallmark trait of cancer, and cancer cells incur increased replication stress and potential for DNA damage as a result. The proteins that mediate cellular responses to DNA damage and replication stress present tumour-specific vulnerabilities for therapeutic intervention.  Checkpoint kinase 1 (CHK1) is a central component of the DNA damage response and repair signalling pathways and CHK1 inhibitors have potential for use as mono-therapy or in combination with other agents. We used structure-based drug design together with mechanistic cellular assays to optimize potent and highly selective small molecule inhibitors of CHK1, leading to the identification of a clinical candidate CHK1 inhibitor.  In parallel, the selective compounds we discovered proved useful as preclinical tools to understand the most effective drug combinations and cancer cell sensitivities to CHK1 inhibition, and to define the contexts for clinical trials.

Discovery of first-in class, selective and noncovalent small molecule inhibitors of DNMT1
Speaker: Allan Jordan
Affiliation: CRUK Manchester Institute

Abstract:

Aberrant DNA hypermethylation is a near universal hallmark of human cancer.  Upon DNA replication, these methylation profiles are copied onto the newly-synthesized DNA strand by DNA methytransferase 1 (DNMT1).Reversal of DNA methyl marks by a hypomethylating agent such as decitabine offers treatment for cancers such as acute myeloid leukemia.  However, considerable drawbacks exist, including IV administration, poor PK, lack of selectivity and incorporation into DNA.  This indirect, irreversible inhibition of the entire DNMT family (DNMT1, 3a and 3b) induces significant dose-limiting toxicity, preventing sufficient target engagement for maximal demethylation. The past few decades have seen considerable interest in the development of potent, selective DNMT1 inhibitors with little, if any, success. Through an industry / not-for-profit collaboration, we have delivered agents which overcome these limitations.  A  high-throughput screen and robust screening cascade revealed a single molecule which was found to be non-DNA incorporating and highly selective for DNMT1 over DNMT3a or DNMT3b.  Optimization of the compound led to compounds that induced decreases in global DNA methylation, activated silenced genes, and inhibited cancer cell growth.  In vivo investigations with these agents decreased DNA methylation and decreased tumor growth at well-tolerated doses, without the toxicity observed with decitabine.