Patrick Griffin, Ph.D.

My scientific career has focused on the study of protein structure and approaches to modulating protein function via synthetic small molecules with a focus on nuclear receptors. I have a broad background in drug discovery and development that spans the last 25+ years. I received a Ph.D. in Chemistry from the University of Virginia under the direction of Professor Donald F. Hunt where I was involved in methodology development in the field of Biological Mass Spectrometry. After graduating from UVa, I was a Postdoctoral Fellow for Professor Leroy Hood at Caltech where I was involved in the application of mass spectrometry to systems biology.

Prior to Scripps, I was Chief Science Officer of ExSAR Corporation, NJ, a biotech company focused the use of HDX mass spectrometry (HDX-MS) to aid in the development of chemical chaperones for protein misfolding disorders. Prior to ExSAR, I was Senior Director, Chemistry, at Merck Research Laboratories where he spent over 11 years applying biological mass spectrometry and proteomics to a wide range of therapeutic areas including metabolic disorders, cardiovascular disease, and infectious diseases. At Merck, I headed the discovery DMPK operation within the Chemistry Department and the Molecular Profiling Proteomics group. My team made significant contributions to over 35 safety assessment programs. Most significant were my team’s contributions towards the discovery and development of MK-0431, a DPP4 inhibitor now in clinical use (Januvia), and towards clinical development of DMP-777, an elastase inhibitor for treatment of cystic fibrosis that progressed to phase IIb trials.

In 2004, I joined The Scripps Research Institute (TSRI) Scripps Florida as Professor and in 2007 was named Professor and founding Chair of the Department of Molecular Therapeutics. As PI, Co-PI, and co-investigator on several NIH-funded grants, my research continues to focus on protein structure and function, particularly on mutational- and ligand-mediated alterations in protein structural plasticity, as well as quantitative SAR to facilitate lead optimization of molecules targeting therapeutic proteins. Using mutagenesis, HDX-MS, crystallography, proteomics and genomics my research is focused on structure-function of nuclear receptors, enzymes, and G protein coupled receptors (GPCRs). My research program has a major focus on understanding nuclear receptor (NR) signaling using structural, chemical and biological approaches. We have made significant contributions to understanding the mechanism of ligand activation of NRs such as PPARs, RORs, REV-ERBs, LRH1, VDR, ER, GR, and PR. We have also made significant contributions dissecting domain-domain interactions in control of positive and negative allostery. Our chemical biology program is focused on the RORs, PPARs, VDR and LRH1. In each of these programs we are developing functionally selective and promoter-specific modulators targeting disease such as cancer, autoimmune, obesity, and diabetes. My lab is well known for the development and application of biophysical methods including our HDX and XL-MS platform for the analysis of protein plasticity with a focus on NRs, enzymes, and GPCRs.

For the first half of my career I was in industry where there was less of an emphasis on publications. However, over the last 16 years as an academic I have published >240 peer-reviewed manuscripts. According to Google Scholar I have an h-index of 83 (58 since 2016) and an i10-index of 223. Below is a URL for My Bibliography of Patrick R. Griffin; some papers are under Griffin P.

As a graduate student at the University of Virginia, I worked in Don Hunt’s lab alongside John Yates and together we performed ground-breaking studies in the use of mass spectrometry to determine the primary structure of proteins. I am first author on a paper describing the complete sequence of a protein using tandem mass spectrometry. Prior, only a few small proteins for which their amino sequence was known had been sequenced by tandem mass spectrometry. This work helped validate that it was possible to sequence proteins using tandem mass spectrometry. I am first author on one of the first papers describing the using low nano-LC coupled with ESI. I contributed to many other publications demonstrating the use of mass spectrometry for structural analysis of proteins.

While at Merck Research Laboratories, my lab made significant contributions to a wide range of projects including key contributions to the development of the DPP4 program which led to the approval and marketing of Januiva. The range of contributions to drug discovery and development are exemplified in manuscripts listed below. My efforts in drug discovery have continued in the academic setting.

In 2002 I became interested in the application of hydrogen/deuterium exchange mass spectrometry. My lab focused on the development of a fully automated system, advanced software to facilitate robust high precision analysis, and applications of HDX in protein-ligand interactions with an emphasis on nuclear receptors, enzymes, and GPCRs. The publications listed below include an extensive list of key contributions to the HDX field.

In addition to the advancement of structural proteomics, my research has focused on chemical biology approaches to better understand nuclear receptor signaling. Our group described the first synthetic ligand for the orphan nuclear receptor NR1F subfamily (ROR)s and subsequently showed the utility of advanced compounds as anti-inflammatory and anti-obesity agents as well as RORG agonists for enhancing protective immunity in the context of cancer therapy. Our lab has also contributed to a fundamentally new understanding of the mechanism by which the nuclear receptor PPARG impacts insulin sensitivity.

Highlights on grant funding related to drug development programs

• I was consortium PI of the “The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps,” I had both a leadership role and a scientific role on this large multi-center 6-year U54 MLPCN Roadmap initiative.

• I was consortium PI of a RC4 program in collaboration with Bruce Spiegelman at the Dana Faber, I was involved in the discovery and development of novel molecules for the treatment of obesity and diabetes. Work from our labs in this area led us to co-found Ember, a private biotech funded by Third Rock Ventures.

• I was Co-PI on a NIDA funded U19 NCDDDG focused on the discovery and development of novel positive allosteric modulators of GABAB receptor for treatment of nicotine addiction.

• I served on the Scripps-Pfizer collaboration Steering Committee for its 5 year term coordinating collaborative drug discovery programs.

• I am PI of a 13-year long collaboration between my lab and Eli Lilly. • I am PI on a collaborative grant with the private Biotech Synkine Therapeutics.

• I am Co-PI on a NIH Blueprint UH3 titled, “Developing nonmuscle myosin II inhibitors for substance use relapse.” Co-founder of Myosin Therapeutics. The Myosin Therapeutics’ clinical candidate emerged from the NIH Blueprint program.

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