Selective Small-Molecule Inducers of ABCA1 as Multifunctional Therapeutics

Project: Research

Investigators

  • Cutler Lewandowski (PI)

Description

Type 2 diabetes mellitus (T2D) is a major cause of morbidity and mortality among Americans. Many cases are inadequately managed with current therapies, resulting in complications such as neurologic, vascular, and heart disease. Thus, an unmet need exists for new treatments that better address T2D pathology and prevent progression to severe complications. One proposed strategy to address this need is to increase expression of ATP-binding cassette member A1 (ABCA1). ABCA1 adds cholesterol to high-density lipoprotein (HDL) particles, improving cholesterol transport in plasma and maintaining lipid homeostasis in body tissues. ABCA1 activity is diminished in T2D patients, while increasing ABCA1 expression reverses multiple aspects of T2D pathophysiology, such as insulin resistance, inflammation, and atherosclerosis. Thus, one ABCA1-inducing drug could provide multifunctional benefit. However, prior attempts to increase ABCA1 expression, via activation of liver X receptors (LXR) transcription factors, resulted in adverse effects, such as increased liver triglyceride (TG) synthesis downstream of the transcription factor SREBP1c. Thus, non-specific agonism corrects T2D phenotypes, but also causes hypertriglyceridemia and liver steatosis. This project aims to develop selective small molecules that upregulate ABCA1 expression with no induction of SREBP1c. With a preliminary lead compound demonstrating only moderate potency but promising efficacy in hand, this study seeks to complete the ongoing hit-to-lead optimization and establish those optimized leads as therapeutic candidates for T2D. Synthetic chemistry guided by existing data and in silico methods will yield potent, selective ABCA1 inducers to be screen in vitro prior to progressing to in vivo characterization. Full PK/PD profiling in mice will assess oral bioavailability and selective target engagement, enabling selection of 1-2 leads for long-term studies. The final phase will use high-fat diet mice as a T2D model to evaluate efficacy and safety of the optimized leads, positioning them for future clinical drug development. Through this multifaceted project, the applicant will receive training in research disciplines spanning the entire preclinical drug discovery process, with guidance from multiple faculty mentors. He will have numerous opportunities for presentation and publication, along with exposure to clinical activities, that will provide a solid foundation for a future physician-scientist career.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35150022
Effective start/end date01/01/202012/31/2021
StatusActive