2. Academic Validation
  3. A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer

A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer

  • Cancer Res. 2022 Oct 17;82(20):3830-3844. doi: 10.1158/0008-5472.CAN-22-0698.
Kristin A Altwegg 1 2,  Suryavathi Viswanadhapalli 1 2,  Monica Mann 1,  Dimple Chakravarty 3,  Samaya Krishnan 1,  Zexuan Liu 1 4,  Junhao Liu 1 4,  Uday P Pratap 1 2,  Behnam Ebrahimi 1 2,  John R Sanchez 1,  Xiaonan Li 1,  Shihong Ma 5,  Ben H Park 6,  Bindu Santhamma 7,  Yidong Chen 8 9,  Zhao Lai 9 10,  Ganesh V Raj 5,  Yaxia Yuan 11,  Daohong Zhou 11,  Gangadhara R Sareddy 1 2,  Rajeshwar R Tekmal 1 2,  Stan McHardy 12,  Tim H-M Huang 2 10,  Manjeet K Rao 2 9,  Hariprasad Vankayalapati 13,  Ratna K Vadlamudi 1 2 14
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, Texas.
  • 2 Mays Cancer Center, UT Health San Antonio, San Antonio, Texas.
  • 3 Department of Urology, Weill Cornell Medical School, New York, New York.
  • 4 Department of Oncology, Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China.
  • 5 Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
  • 6 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 7 Evestra.Inc, San Antonio, Texas.
  • 8 Department of Population Health Sciences, UT Health San Antonio, San Antonio, Texas.
  • 9 Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, Texas.
  • 10 Department of Molecular Medicine, UT Health San Antonio, San Antonio, Texas.
  • 11 Department of Biochemistry and Structural Biology, and Center for Innovative Drug Discovery, UT Health San Antonio, San Antonio, Texas.
  • 12 Department of Chemistry and Center for Innovative Drug Discovery, University of Texas San Antonio, San Antonio, Texas.
  • 13 Utah Health Huntsman Cancer Institute, Salt Lake City, Utah.
  • 14 Audie L. Murphy South Texas Veterans Health Care System, San Antonio, Texas.
PMID: 35950923 DOI: 10.1158/0008-5472.CAN-22-0698
Abstract

Most patients with Estrogen Receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast Cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these Peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast Cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast Cancer cells, in part by inducing PELP1 degradation via the Proteasome pathway. RNA Sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and Apoptosis pathways. In cell line-derived and patient-derived xenografts of both WT and MT ER+ breast Cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast Cancer.

Significance: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast Cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169903
    PELP1抑制剂
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