2. Academic Validation
  3. Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer

  • J Med Chem. 2021 Sep 9;64(17):12831-12854. doi: 10.1021/acs.jmedchem.1c00882.
Xin Han 1 2,  Lijie Zhao 1 2,  Weiguo Xiang 1 2,  Chong Qin 1 2,  Bukeyan Miao 1 2,  Donna McEachern 1 2,  Yu Wang 1 2,  Hoda Metwally 1 2,  Lu Wang 3,  Aleksas Matvekas 3,  Bo Wen 3,  Duxin Sun 3,  Shaomeng Wang 1 2 4 5
Affiliations

Affiliations

  • 1 The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 34431670 DOI: 10.1021/acs.jmedchem.1c00882
Abstract

Proteolysis targeting chimera (PROTAC) small-molecule degraders have emerged as a promising new type of therapeutic agents, but the design of PROTAC degraders with excellent oral pharmacokinetics is a major challenge. In this study, we present our strategies toward the discovery of highly potent PROTAC degraders of Androgen Receptor (AR) with excellent oral pharmacokinetics. Employing thalidomide to recruit Cereblon/cullin 4A E3 ligase and through the rigidification of the linker, we discovered highly potent AR degraders with good oral pharmacokinetic properties in mice with ARD-2128 being the best compound. ARD-2128 achieves 67% oral bioavailability in mice, effectively reduces AR protein and suppresses AR-regulated genes in tumor tissues with oral administration, leading to the effective inhibition of tumor growth in mice without signs of toxicity. This study supports the development of an orally active PROTAC AR degrader for the treatment of prostate Cancer and provides insights and guidance into the design of orally active PROTAC degraders.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z