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In Vivo Proof of Concept and Target Identification Using Small Molecule Stimulators of Brown Adipogenesis

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44DK125193-02
Agency Tracking Number: R44DK125193
Amount: $1,988,528.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 300
Solicitation Number: PA20-260
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-08-01
Award End Date (Contract End Date): 2023-07-31
Small Business Information
Boston, MA 02199-7723
United States
DUNS: 831412205
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (617) 959-2322
Business Contact
Phone: (617) 437-0881
Research Institution

Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2
diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non-
surgical treatments. While most current weight loss agents act by suppressing appetite, strategies that can
safely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT)
is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein
dissipates, in a regulated fashion, the electrochemical gradient in the mitochondria of brown adipocytes as
heat, and thus plays an important role in the maintenance of body temperature and energy balance in
rodents and humans. BAT is a flexible tissue that normally enlarges or atrophies over time depending on
environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly
been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be
effectively nonexistent in adult humans, data obtained in the past several years show that adults in fact have
significant BAT and that this tissue is functional. It has been well established that a higher amount of active
BAT in individuals is strongly correlated with leanness. Cold exposure in humans leads to increased BAT
formation, thermogenesis, insulin sensitivity, and lipolysis, demonstrating that BAT can be recruited and lead
to metabolic benefits. Moreover, the genetic locus most tightly linked with general obesity causes defective
recruitment of new brown adipocytes.
Until recently no brown adipocyte stem cell had been identified. We discovered human brown adipocyte
progenitor cells that under appropriate conditions become fully functional brown adipocytes, with high levels
of UCP1 and a very high metabolic rate. These cells are a unique tool that we used to develop an assay for
identifying compounds with the capacity to recruit new BAT. We recently used this assay for high throughput
screening and obtained several high quality hits with good activity, potency, and analogability. We have now
created a series of novel analogs of the best hits with excellent activity and desirable physicochemical and
ADME properties.
In the proposed work, we aim to demonstrate in vivo proof of concept with this series of analogs by studying
the compounds' pharmacokinetics and efficacy in a high quality mouse model of obesity and insulin
resistance. We will also investigate the molecular mechanism of the compound series. If this work is
successful we plan to advance to compound optimization, selection of a development candidate and backup,
and generation of IND-enabling safety data.

* Information listed above is at the time of submission. *

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