Nathanael Gray is a Professor of Chemical and Systems Biology at Stanford, Co-Director of Cancer Drug Discovery, Co-Leader of the Cancer Therapeutics Research Program, Member of Chem-H, and Program Leader for Small Molecule Drug Discovery for the Innovative Medicines Accelerator (IMA). His research uses the tools of synthetic chemistry, protein biochemistry, and cancer biology to discover and validate new strategies for addressing anti-cancer targets. Dr. Gray’s research has had broad impact in the areas of kinase inhibitor and degrader design and in circumventing drug resistance. Dr. Gray’s generalized strategy for structure-based design of inhibitors that stabilize the inactive kinase conformations (type II) has been widely adopted by the research community and has had a significant impact on the development of numerous inhibitors of tyrosine kinases that are currently undergoing clinical development.
Dr. Gray received his PhD in organic chemistry from the University of California at Berkeley in 1999 after receiving his BS degree with the highest honor award from the same institution in 1995. During his PhD work, Dr. Gray developed new combinatorial chemistry and functional genomics approaches that resulted in the discovery of Purvalanol, one of the first selective inhibitors of cyclin-dependent kinases. After completing his PhD, Dr. Gray was recruited to the newly established Genomics Institute of the Novartis Research Foundation (GNF) in San Diego, California. During his six year stay at GNF, Dr. Gray became the director of biological chemistry. Among other accomplishments, his team discovered the first allosteric inhibitors of wild-type and mutant forms of BCR-ABL which resulted in clinical development of ABL001, and the first selective inhibitors of the Anaplastic Lymphoma Kinase (ALK), an achievement that led to the development of now FDA-approved drugs such as ceritinib (LDK378) for the treatment of EML4-ALK expressing non-small cell lung cancer (NSCLC). Beyond oncology, Dr. Gray’s team revealed that sphingosine-1-phosphate receptor-1 (S1P1) is the pharmacologically relevant target of the immunosuppressant drug Fingomilod (FTY720) followed by the development of Siponimod (BAF312), which is currently used for the treatment of multiple sclerosis.
In 2006, Dr. Gray joined faculty of the Dana Farber Cancer Institute and Harvard Medical School in Boston. There, he established a discovery chemistry group that has been focusing on developing first-in-class pharmacological agents for newly emerging biological targets, including resistant alleles of existing targets, as well as well-validated targets, such as Her3 and RAS, that have previously been considered recalcitrant to small molecule drug development. Additionally, his group has been employing these novel small molecule tools to investigate the therapeutic potential of a range of targets in cancer. His success in developing and translating experimental anti-cancer agents has been due to his highly collaborative and integrative approach to research, as Dr. Gray has developed and led large project teams that combine expertise in structural biology, biochemistry, cancer cell biology, and translational research. Dr. Gray has also built a reputation as a strong partner for commercial entities needed to further clinical development, resulting in establishment of number of companies. For example, Dr. Gray’s development of covalent inhibitors for the T790M mutant EGFR inspired the development of Osimertinib (AZD9291), now FDA approved for treatment of patients with relapsed lung cancer due to resistance to first generation EGFR inhibitors. Dr. Gray has also developed structure-based, generalizable approaches for designing drugs to overcome one of the most common mechanisms of kinase drug resistance, mutation of the so-called “gatekeeper” threonine (T) residue. This approach has resulted in development of Ponatinib, a drug that overcomes T315I gatekeeper mutant of BCR-ABL. Amongst the additional notable achievements of Dr. Gray’s research laboratory are: development of the first ATP-competitive mTor inhibitor, Torin1, and its use to discover that rapamycin is an incomplete inhibitor of mTOR; development of the first inhibitors of ERK5 (BMK1), which are currently under preclinical development; development of efficient approaches for the discovery of covalent kinase inhibitors that have contributed to the resurgence of interest in this approach; development of the first selective inhibitors of LRRK2, a kinase that is activated by point mutations in a subset of sporadic and familial cases of Parkinson Disease; and discovery of the first potent and selective inhibitors of BCR-ABL, FGFR, MPS1, JNK and BMX which have resulted in new insights into their function and, in several cases, inspired drug discovery efforts. Dr. Gray’s research team developed approaches to covalently target CDK7 and CDK12, key regulators of gene transcription, and compounds inspired by these efforts are approaching clinical trials. Dr Gray’s lab has been involved with developing small molecule protein degraders, especially their application towards degrading protein kinases. The impact of these new pharmacological agents is amplified by the laboratories approach to ‘open-source’ discovery: all the compounds are made immediately available to any interested researchers with no strings attached.
Dr. Gray has also been involved in establishing new companies to advance projects from the lab into the commercial sector including: Gatekeeper (acquired), Petra, Syros (IPO), C4, Soltego, B2S, Allorion and Jengu Therapeutics.
These contributions have been recognized through numerous awards including the National Science Foundation’s Career award in 2007, the Damon Runyon Foundation Innovator award in 2008, the American Association for Cancer Research for Team Science in 2010 and for Outstanding Achievement in 2011, the American Chemical Society award for Biological Chemistry in 2011, and the Nancy Lurie Marks endowed professorship in 2015 and the Paul Marks Prize in 2019.
