2. Academic Validation
  3. Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss

Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss

  • J Med Chem. 2021 Feb 25;64(4):2046-2063. doi: 10.1021/acs.jmedchem.0c01570.
Xiaoguang Liu 1,  Aimee A Flores 2 3 4,  Lisa Situ 2 5,  Wen Gu 6,  Hui Ding 1,  Heather R Christofk 6 7 3 5,  William E Lowry 2 7 3 4,  Michael E Jung 1 6
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, UCLA, 607 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 2 Department of Molecular Cell and Developmental Biology, UCLA, 610 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 3 Eli and Edythe Broad Center for Regenerative Medicine, UCLA, 615 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 4 Molecular Biology Institute, UCLA, 611 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 5 Department of Biological Chemistry, UCLA, 615 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 6 Department of Molecular and Medical Pharmacology, UCLA, 650 Charles E Young Dr E, Los Angeles, California 90095, United States.
  • 7 Jonsson Comprehensive Cancer Center, UCLA, 10833 Le Conte Ave, Los Angeles, California 90024, United States.
PMID: 33534563 DOI: 10.1021/acs.jmedchem.0c01570
Abstract

Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both in vitro and in vivo for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than JXL001 (UK-5099) to increase cellular lactate production. Additionally, analogue JXL069, possessing a 7-azaindole heterocycle, was also shown to have significant MPC inhibition activity, which further increases the chemical space for drug design. Finally, more than 10 analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.

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