Kenneth A. Jacobson, Ph.D.

Research Goal

Our overall goals are to design and chemically synthesize novel, potent, and selective ligands to probe the function of purinergic receptors (adenosine, P2Y and P2X receptors) and other critical cell-surface proteins, including other G protein-coupled receptors, ion channels, enzymes, and transporters. Our laboratory uses an interdisciplinary approach that integrates medicinal chemistry, computational modeling, and structural biology to create advanced pharmacological tools and to identify new therapeutic agents for a wide range of human diseases.

Current Research

Our work is driven by the goal of translating fundamental discoveries in molecular pharmacology into clinical candidates. By elucidating the three-dimensional structures of our protein targets—often in collaboration with leading structural biologists—we guide the rational design of new molecules with optimized efficacy and selectivity. This structure-based approach has been instrumental in our success, leading to landmark structural discoveries and multiple compounds advancing into clinical trials.

Key Research Areas & Recent Accomplishments

Our research program is organized around three major families of drug targets, with a strong focus on translating our discoveries into treatments for chronic diseases.

1. Adenosine Receptor (AR) Agonists and Antagonists

We develop subtype-selective ligands for the four adenosine receptors to treat inflammatory diseases, cancer, and neurological disorders. Our A₃AR agonists have been particularly successful, advancing from basic research to clinical application.

• Clinical Translation: Two of our A₃ adenosine receptor agonists, IB-MECA and Cl-IB-MECA, are in Phase 3 clinical trials for their anti-inflammatory and anticancer properties. A third compound, MRS4322, has entered a Phase 2 trial for treating concussion and traumatic brain injury, addressing a major unmet medical need.
• Neuropathic Pain: In collaboration with Dr. Daniela Salvemini, we developed highly selective A₃ receptor agonists that are more potent than morphine in animal models of chronic neuropathic pain, offering a potential non-opioid solution for this debilitating condition. They also reduce the side effects of morphine, making it safer and preserving its antinociceptive property over time.
• Targeted Therapies: We have engineered a novel, light-activated prodrug of an A₃ agonist that selectively reduces inflammation in psoriatic skin lesions upon irradiation, demonstrating a new paradigm for targeted therapy.

2. P2Y Receptor Ligands for Metabolic and Inflammatory Diseases

Our laboratory develops subtype-selective agonists and antagonists for the eight P2Y nucleotide receptors. This work has uncovered new therapeutic concepts for diabetes, asthma, and chronic pain.

• Metabolic Disease: We established the P2Y₆ and P2Y₁₄ receptors as critical regulators of metabolism. In preclinical models, genetic deletion or pharmacological blockade of these receptors in fat tissue protects against diet-induced obesity, liver steatosis, and insulin resistance. We are advancing potent antagonists for these targets as potential treatments for Type 2 Diabetes.
• Inflammation, Asthma and Pain: We discovered a feedback loop in which the P2Y₁₄ receptor amplifies eosinophilic inflammation. Our potent P2Y₁₄ R antagonists successfully inhibit this pathway in preclinical models, revealing a novel strategy for treating steroid-resistant asthma. P2Y₁₄ R antagonists also reduce chronic neuropathic pain in model systems.
• Structural Biology: Our synthetic ligands have been critical for solving the first-ever crystal structures of the P2Y₁ and P2Y₁₂ receptors, as well as the recent cryogenic electron microscopic (cryo-EM) structure of the P2Y₁₄ receptor, providing a blueprint to enable future drug design.

3. Modulators of Ion Channels and Transporters

We design and synthesize novel ligands for ion channels and transporters to address cardiovascular disease, stroke, and drug resistance in cancer.

• Heart Failure: In collaboration with Dr. Bruce Liang, we identified an atypical P2X4 receptor agonist, MRS2339, which improves cardiac function and increases lifespan in preclinical models of heart failure. This compound is now being licensed for clinical development.
• Stroke Neuroprotection: We developed a highly potent P2X4 receptor antagonist, MRS4719, which reduces brain inflammation and improves cognitive outcomes in a mouse model of ischemic stroke.
• Breakthrough in Structural Biology: We developed the first allosteric modulators of the dopamine transporter (DAT). One of our compounds, MRS7292, was instrumental in enabling our Dr. Eric Gouaux and colleagues to solve the first high-resolution cryo-EM structure of the human DAT, which can be applied to understanding stimulant addiction and designing new therapies.

Applying our Research

Our selective receptor ligands are used as pharmacological probes of the role of extracellular nucleosides and nucleotides in the brain and in peripheral tissues. More than 50 compounds from our lab are available commercially as research tools and are used to advance research in hundreds of laboratories. (PDF, <1 MB) Our own internal studies and outside collaborations include studies of the role of these receptors, and possible treatments for, thrombosis, Parkinson’s disease, inflammatory diseases, cancer, diabetes, chronic neuropathic pain, and epilepsy.

Need for Further Study

The multifaceted relationship between drug structure and biological activity requires further probing. The study of GPCRs, including purinergic receptors, provide promising avenues for the development of new drug therapy for treating chronic diseases.

• Chief, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, 1993-present
• Chief, Laboratory of Bioorganic Chemistry, NIDDK, 2008-2018
• Bantrell Fellow, Weizmann Institute of Science, Department of Organic Chemistry, 1983
• Ph.D., University of California, San Diego, 1981
• M.S., University of California, San Diego, 1978
• B.A., Reed College, 1975