Pete Rahl

- NextRNA Therapeutics - worked with leadership team to optimize the company pipeline and perform diligence on potential in-licensing opportunities - Identified opportunity to initiate a new drug discovery program in a new disease area for the company with the potential to rapidly nominate a Development Candidate. Led the efforts with the team to build an aggressive and streamlined research plan to validate the target and progress drug discovery towards Development Candidate nomination.

 Lead group of scientists, averaging 6-10 scientists, that executed discovery biology research (including target validation, target nomination, screen triage) and cellular pharmacology research (including target engagement, downstream pharmacodynamics, kinetic analyses and genomic mechanism of action studies). Operated within highly integrated and cross-functional research teams.  Member of the Discovery Leadership Team involved in developing and executing the research strategy of the company to support pipeline progression from early-stage company to publicly traded company ($KRON). Activities included setting research strategy and goals, distributing and adjusting resources across programs, driving teams towards timely project decision points, and communicating progress and decisions to the executive team and research team.  Identified a strategic opportunity to initiate a quick-start program targeting a well-established gene regulatory protein that is a key cofactor for multiple oncogenic transcription factors. Led the due diligence team that realized it was an under-appreciated drug target and would fill a key pipeline gap. The diligence found that it could be a valuable drug target in multiple cancer types with unmet medical need. Helped build the research program and form the project team that went from hit-to-lead to DC nomination, KB-9558, in about 2 years. Member of the clinical development team involved in IND drafting and clinical development plan for KB-9558.  Project lead on inflammation project that resulted in the nomination of DC KB-7898 as an orally available, small molecule therapy for use in chronic inflammatory diseases and autoimmune diseases. Worked with the research team to establish a suite of ex vivo and in vivo models to determine the molecular mechanism of action to drive indication selection.  Mentored and trained scientists across multiple levels, trained new people managers and new project leads.

 Developing novel small molecule therapeutics for the treatment of devastating developmental disorders using patient-derived cellular models. We use directed differentiation of induced pluripotent stem cell (iPS) and progenitor stem cell models to identify gene expression regulators of disease driver genes. Patient-derived neurons, skeletal muscle and red blood cells are used to identify strategies to the reverse pathophysiology in relevant patient derived cell types.  Scientific Team Lead in developing a small molecule drug for the treatment of Sickle Cell Disease and other hemoglobinopathies; DC expected in 2019. My team executed chemical probe and pooled CRISPR cell-based screens to identify a pipeline of potential targets in SCD that led to a Lead Optimization discovery project and multiple backup projects. I have been heavily involved in business development discussions for partnerships related to this project.  Members of my team identified and validated Fulcrum’s lead target in Facioscapulohumeral Muscular Dystrophy and rapidly progressed from target identification using a cell-based screen to target validation to DC in less than one year.  Target Validation lead to identify novel drug targets and develop small molecules that modulate the expression of disease driver genes. We are using iPS and differentiated models of Fragile X Syndrome, Facioscapulohumeral Muscular Dystrophy, Sickle Cell Anemia and other monogenic diseases to identify and validate targets using CRISPR and small molecule probe strategies in cell-based assays. These diseases are caused by genetic mutations in a specific disease-associated gene and the disease can be alleviated through modulating a specific gene expression pattern.  Utilizing multiple genomics approaches, including ChIP-seq, ATAC-seq and RNA-seq, to characterize patient-derived cellular models and investigate target mechanism of action.  Managing a team of 6 scientists that is working across disease indications.

 Helped start Syros Pharmaceuticals to use insights into cancer’s molecular circuitry to develop novel therapies to modulate their cell state. As a founding scientist, I played a key role to shape the research strategy, attract talented personnel and assemble the laboratory in order to meet aggressive goals and get the company off the ground. Syros has grown into a publicly traded company (IPO in July 2016 - $SYRS:NASDAQ) and has two drugs in clinical trials for oncology indications.  Led the drug discovery program targeting a protein:nucleic acid complex. I developed the research plan and key technologies to initiate small molecule screening (executed 2 biochemical high throughput screens; 1 internal, 1 with an external CRO) and hit triage and advanced one chemical scaffold to hit-to-lead optimization. We decided as a team to end this project prior to transition to lead optimization due to a lack of clear understanding of the molecular recognition of the ligand to the protein/nucleic acid complex.  Established the biology research plan to guide medicinal chemistry for developing inhibitors against a new oncology target, CDK7, and identifying potential indications for these compounds. This project is in Phase I clinical trials in a molecularly defined patient population.  Worked with contract researcher organizations and established collaborations with academic and industry researchers.  Managed a team of 2-3 scientists that focused on assay development and medicinal chemistry optimization of a kinase target and protein:nucleic acid complex.  Syros provided me with a unique experience to be involved with starting and growing a company into a publicly traded company where I can directly impact the lives of patients and gave me the foundation to lead a team of highly talented scientists to develop new oncology drugs against the most potent, and most challenging, oncogene in human cancer.

 Syros Pharmaceuticals was founded on technology and concepts developed at the Whitehead Institute and Dana Farber Cancer Institute. I helped develop many of these and was a co-inventor on multiple patents licensed to Syros.  Presented work to one of the early investing venture capital firms. I was hired as a scientific consultant to transition the innovative technologies to Syros. I worked directly with the acting CEO and other consultants to help develop the scientific strategy and get the company off the ground. We met our goal of starting the company on Jan 2, 2013.  Transformed the empty lab space into a fully operational lab. This included determining the equipment needed to run the array of experiments, outfitting the lab space with the necessary equipment within a budget, assembling or directing assembly of lab equipment and performing the first experiment.

As a visiting scientist, I am finishing studies from Rick Young's lab investigating global transcriptional regulatory mechanisms in disease and using these insights for targeted therapy.

 Every cell in the human body contains the same DNA with the same genes, but the pattern of which genes are on or off is the key determinant of cell identity. Defects in this regulation (transcriptional regulation) often cause disease.  My research aimed to understand transcriptional regulatory networks during normal development and disease using different types of stem cells and disease models, including blood cancers, melanoma, autoimmunity and obesity. In collaboration with chemists and clinicians at Harvard Medical School (HMS) we used these insights to target deregulated pathways in specific diseased cells with targeted drugs. This work has led to multiple clinical trials, including in melanoma, multiple myeloma and diffuse large B cell lymphoma.  Used stem cells as a system, serving as a ground state for developmental potential, to discover a key proliferation pathway in stem cells, driven by the prolific oncogene MYC, where gene expression is regulated through transcriptional pause release. This work used a combination of molecular biology and systems biology to understand how internal and external signals influence the cell's state.  The stem cell findings were expanded to cancer where we discovered that cancers overexpressing the oncoprotein MYC amplify their transcriptional program, which is likely how it acts as a powerful oncogene. In collaboration with researchers and clinicians at Dana Farber Cancer Institute (DFCI) and HMS, we translated these mechanistic systems biology insights to develop novel anticancer strategies to target the deregulated MYC pathway.

 Controlling the transport of the appropriate constellation of molecules to the cell periphery is critical for a wide variety of cellular functions including cell-cell communication, neuronal function, immune cell function and host or pathogen infection.  Familial Dysautonomia is a human genetic disorder caused by defects in neuronal migration leading to neurodegeneration. Mutations in the IKAP gene cause these defects but the molecular link between mutation and phenotype through IKAP function is poorly understood.  Using yeast as a model system, I uncovered a novel role for IKAP in regulating intracellular transport. We found that IKAP and its associated acetyltransferase complex is a negative regulator of exocytosis, a process that regulates the delivery of material for growth and migration to the cell surface.

 When taken orally, drugs differ in their absorption and solubility characteristics as they transit through the gastrointestinal tract. Understanding the limiting factors can aid future drug design and formulation. For example, some compounds exhibit drastic changes in solubility as they travel from the acidic environment of the stomach to the more neutral environment of the intestines, where the majority of oral drugs are absorbed.  Developed an in vitro model to simulate the changes in pH from the stomach to the intestines to study compound precipitation kinetics. This model, using high performance liquid chromatography as a readout, now offers an in vitro option to study a panel of candidate compounds and help prioritize compounds for further in vivo testing.  Compound solubility and stability can be a limitation in drug development. The compounds will not be clinically useful if they are not soluble or stable over time.  Worked in an analytical chemistry group to generate and study salt derivatives of compounds to deal with solubility and stability issues. I grew single crystals of new compounds to allow us to study their atomic structure using xray crystallography and used near infrared spectroscopy to analyze the composition of the new salts.

Department of Molecular Medicine