capitalize on the full range of possible chromatin targets in and beyond
oncology, industry and academia will need to delve deeper into how chromatin
regulation is altered in disease, create tools that can reliably validate new
targets and develop biomarkers that can improve the chances of success in
first DNMT and HDAC inhibitors were developed when knowledge of chromatin
regulation was sparse at best. Indeed, compounds that inhibit these targets
were shown to have anticancer properties. Only later
were their mechanisms of action established.
was wide agreement among panel members that the field needs more and better
chemical probes to understand how dysfunctional chromatin regulators contribute
Another major challenge highlighted by the panelists is the
lack of predictive biomarkers that could help explain the cellular effects of
inhibiting particular chromatin targets. That lack of biomarkers has made it
difficult to expand into cancers with no known genomic alterations.
Panelists agreed that expanding chromatin-targeted drug
development beyond genomically altered cancers will require increased
commitment to chromatin profiling and follow-up functional studies to test new
chromatin-targeted compounds are starting to produce results in cancer,
applications in non-oncology indications are still far behind. For existing
targets such as HDACs and BET bromodomains, developing selective compounds with
appropriate safety profiles for chronic use remains a prime challenge.
The panel and audience members returned frequently to a
discussion of clinical development challenges for compounds targeting chromatin
The next frontier
Finally, panelists discussed the prospects for developing
compounds that act by causing cells to differentiate into other cell types
rather than by killing cells.
Cain, C. SciBX 7(19); doi:10.1038/scibx.2014.545
Published online May 15, 2014
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AND INSTITUTIONS MENTIONED
Acetylon Pharmaceuticals Inc., Boston, Mass.
(NASDAQ:AMGN), Thousand Oaks, Calif.
Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan
(LSE:AZN; NYSE:AZN), London, U.K.
Biogen Idec Inc.
(NASDAQ:BIIB), Weston, Mass.
Broad Institute of MIT and Harvard, Cambridge, Mass.
Cancer Research UK Manchester Institute, Manchester, U.K.
Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, Japan
Constellation Pharmaceuticals Inc., Cambridge, Mass.
Dana-Farber Cancer Institute, Boston, Mass.
(NASDAQ:EPZM), Cambridge, Mass.
Forma Therapeutics Holdings LLC, Watertown, Mass.
South San Francisco, Calif.
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.
Harvard Medical School, Boston, Mass.
Harvard University, Cambridge, Mass.
Howard Hughes Medical Institute, Chevy Chase, Md.
Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.
Karus Therapeutics Ltd., Chilworth, U.K.
Massachusetts General Hospital, Boston, Mass.
Massachusetts Institute of Technology, Cambridge, Mass.
Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.
(NYSE:NVS; SIX:NOVN), Basel, Switzerland
Novartis Institutes for BioMedical Research, Cambridge, Mass.
Oryzon Genomics S.A., Barcelona, Spain
RaNa Therapeutics Inc., Cambridge, Mass.
(TSX:RVX), Calgary, Alberta, Canada
(SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
Rodin Therapeutics Inc., Cambridge, Mass.
(Euronext:SAN; NYSE:SNY), Paris, France
Structural Genomics Consortium, Oxford, U.K.
Syros Pharmaceuticals Inc., Watertown, Mass.
Tensha Therapeutics Inc., Cambridge, Mass.
Thermo Fisher Scientific Inc. (NYSE:TMO), Waltham, Mass.
Whitehead Institute for Biomedical Research, Cambridge, Mass.
Zenith Epigenetics Corp., Calgary, Alberta, Canada