The National Institute of Allergy and Infectious Diseases (NIAID) recently awarded BellBrook Labs a $1.8 million Phase II Small Business Innovative Research (SBIR) grant to develop small molecule antagonists of cyclic GAMP synthase (cGAS). The grant will enable BellBrook to optimize their cGAS lead molecules and test their efficacy for treating lupus-related UV light sensitivity in collaboration with Dr. Keith Elkon at the University of Washington, Seattle.
Madison, WI – April 20, 2021 – BellBrook Labs has been awarded a $1.8 million Phase II SBIR grant by the National Institute of Allergy and Infectious Diseases (NIAID) to develop lead molecules that block cyclic GAMP synthase (cGAS) for the treatment of lupus and other autoimmune diseases. BellBrook’s CEO, Dr. Robert Lowery is the principal investigator for the effort, and Dr. Keith Elkon, Head of Rheumatology at the University of Washington, Seattle, is a collaborator.
Lupus is the second most common autoimmune disease, affecting more than 300,000 people in U.S, with 16,000 new cases annually. Lupus patients suffer from various symptoms, including skin lesions, arthritis, and fatigue; it strikes women much more frequently than men. Though the disease can be mild, lupus causes major organ damage in 50% of cases; e.g., heart, lung, kidneys, brain, and results in a 67% increase in mortality. The underlying cause of lupus is constitutive over-activation of the immune system driven by a class of potent immune signaling molecules called type I interferons.
Cyclic GAMP synthase (cGAS) is the trigger for autoimmunity: it senses DNA released from damaged cells. It produces signaling molecules that activate the pathway for the production of interferons, which circulate throughout the body, activating the immune system to attack critical organs and tissues. Multiple lines of evidence, including genetic knockouts of cGAS in mouse models of monogenic lupus, have clearly established that blocking cGAS is a compelling therapeutic strategy for lupus and other interferon-driven autoimmune diseases.
BellBrook is using structure-based design to develop two cGAS inhibitors with distinct mechanisms and organ distribution profiles. They plan to advance one of the molecules as a therapy for lupus and the other for treatment of Aicardi Goutieres syndrome, a rare childhood encephalopathy. The molecule being developed for lupus will be tested for in vivo efficacy in an innovative model of lupus-induced UV skin sensitivity developed by their collaborator, Dr. Keith Elkon.
The cGAS inhibitor program was enabled by the development of a proprietary biochemical HTS assay funded by a Phase I NIH SBIR grant awarded in April 2017 (grant number R43 GM123833-01), using the same approach that underlies BellBrook’s successful Transcreener HTS Assays. Consistent with their mission, the company recently commercialized the Transcreener cGAMP cGAS Assay to accelerate the discovery of cGAS inhibitors by other groups. The cGAS antagonists will be commercialized by BellBrook’s therapeutics subsidiary, Nudge Therapeutics, Inc.
About BellBrook Labs:
BellBrook Labs is dedicated to accelerating drug discovery and biological research by providing innovative high throughput screening solutions. BellBrook’s core technology Transcreener is a universal, homogenous biochemical assay platform based on detection of nucleotides that makes it easy to screen thousands of different enzymes. These include validated targets like kinases, as well as emerging targets like ATPases, GTPases, methyltransferases, and cGAS. Detection reagents and services from BellBrook Labs help researchers progress toward more effective therapies for cancer and other debilitating diseases.
Research reported in this publication was supported by the National Institute of General Medical Sciences and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers R44GM123833 and R44AI141281, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.