2. Academic Validation
  3. An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer

An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer

  • Cancer Res. 2024 Nov 12. doi: 10.1158/0008-5472.CAN-24-0591.
Tae Hyun Bae 1,  Ki Woon Sung 1,  Tri M Pham 2,  Abdo J Najy 2,  Alaleh Zamiri 2,  Hyejeong Jang 3,  Su Ran Mun 1,  Seongho Kim 4,  Ha Kyoung Kwon 5,  Yeon Sung Son 1,  Dongping Shi 6,  Steven Kregel 7,  Elisabeth I Heath 8,  Michael L Cher 2,  Yong Tae Kwon 9,  Hyeong-Reh C Kim 2
Affiliations

Affiliations

  • 1 Seoul National University, Seoul, Korea (South), Republic of.
  • 2 Wayne State University School of Medicine, Detroit, MI, United States.
  • 3 Karmanos Cancer Institute, Detroit, MI, United States.
  • 4 Wayne State University, Detroit, MI, United States.
  • 5 AUTOTAC Bio Inc., Seoul, Korea (South), Republic of.
  • 6 Wayne State University School of Medicine, Detroit, United States.
  • 7 Loyola University Chicago, Maywood, IL, United States.
  • 8 Karmanos Cancer Center, Detroit, MI, United States.
  • 9 College of Medicine, Seoul National University, Seoul, Korea (South), Republic of.
PMID: 39531508 DOI: 10.1158/0008-5472.CAN-24-0591
Abstract

Genetic alterations play a pivotal role in various human diseases, particularly Cancer. The Androgen Receptor (AR) is a crucial transcription factor driving prostate Cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the Autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.

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