Our understanding of how cancers begin, survive and progress is rapidly expanding through advances in cancer genomics and modern cancer biology. Although these insights suggest many new strategies for therapeutic intervention, they often require modulating targets against which the research community has had little experience or success developing small-molecule probes and drugs. Through the NCI Molecular Target Discovery and Development Center Network Pilot Program, we aim to overcome this challenge and to accelerate the discovery of novel therapeutics in cancer. The Broad-MTDDC will provide over 10 years of experience in both innovation and execution in small- molecule probe and drug development to the MTDDC Network to advance insights from the cancer biology community.
We aim to innovate in fundamental chemistry so as to enable the discovery of small-molecule probes against even 'undruggable'cancer targets such as those emerging from genomic studies;to engage the cancer biology community and to bring small-molecule science to the root causes of cancer;and to solve the target I.D. problem, including by determining comprehensively the proteins to which small-molecule modulators of cancer pathways bind in or on cells. Furthermore, we will provide the cancer biology community with the robust infrastructure and expertise required to execute probe- and drug-development projects that aim to transform cancer therapeutics. Impact on human health. The Molecular Target Discovery and Development Center at the Broad Institute will discover small molecules that target the root causes and dependencies of cancer. These leads will serve as valuable starting points for new drug development programs. By providing early lead optimization and data from clinically relevant animal models, we aim to advance cancer drug discovery development. Furthermore, we will make all data associated with small-molecule probe development publicly available, enabling further discovery from the community and broader communication of our approaches to drug discovery.

Public Health Relevance

The Molecular Target Discovery and Development Center at the Broad Institute will develop and execute small-molecule screens from the cancer biology community aimed at targeting the root causes and dependencies of cancer. We will focus on innovation in chemistry, screening, and preclinical research in order to access targets viewed as 'undruggable'using current tools and approaches. These projects will yield small- molecule probes that both enable pre-clinical validation of therapeutic strategies using animal models and serve as outstanding starting points for drug development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
3RC2CA148399-02S1
Application #
8464829
Study Section
Special Emphasis Panel (ZCA1-SRLB-R (O9))
Program Officer
Gerhard, Daniela
Project Start
2009-09-29
Project End
2013-04-30
Budget Start
2012-09-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$648,750
Indirect Cost
$273,750
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Coleman, Jeffrey J; Komura, Tomomi; Munro, Julia et al. (2016) Activity of caffeic acid phenethyl ester in Caenorhabditis elegans. Future Med Chem 8:2033-2046
Zhang, Zhengjian; Boskovic, Zarko; Hussain, Mahmud M et al. (2015) Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation. Elife 4:
Seashore-Ludlow, Brinton; Rees, Matthew G; Cheah, Jaime H et al. (2015) Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. Cancer Discov 5:1210-23
Johannessen, Cory M; Clemons, Paul A; Wagner, Bridget K (2015) Integrating phenotypic small-molecule profiling and human genetics: the next phase in drug discovery. Trends Genet 31:16-23
Yang, Wan Seok; SriRamaratnam, Rohitha; Welsch, Matthew E et al. (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317-331
Pop, Marius S; Stransky, Nicolas; Garvie, Colin W et al. (2014) A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein. Mol Cancer Ther 13:1492-502
Abazeed, Mohamed E; Adams, Drew J; Hurov, Kristen E et al. (2013) Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Res 73:6289-98
Basu, Amrita; Bodycombe, Nicole E; Cheah, Jaime H et al. (2013) An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules. Cell 154:1151-1161
Raj, Lakshmi; Ide, Takao; Gurkar, Aditi U et al. (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475:231-4
Cancer Target Discovery and Development Network; Schreiber, Stuart L; Shamji, Alykhan F et al. (2010) Towards patient-based cancer therapeutics. Nat Biotechnol 28:904-6