2. Academic Validation
  3. EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer

EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer

  • Mol Cancer Ther. 2019 Aug;18(8):1341-1354. doi: 10.1158/1535-7163.MCT-18-1258.
Suryavathi Viswanadhapalli 1,  Yiliao Luo 1 2,  Gangadhara R Sareddy 1 3,  Bindu Santhamma 4,  Mei Zhou 1 5,  Mengxing Li 1 6,  Shihong Ma 7,  Rajni Sonavane 7,  Uday P Pratap 1,  Kristin A Altwegg 1,  Xiaonan Li 1,  Annabel Chang 7,  Alejandra Chávez-Riveros 4,  Kalarickal V Dileep 8,  Kam Y J Zhang 8,  Xinlei Pan 9,  Ramachandran Murali 9,  Marek Bajda 10,  Ganesh V Raj 7,  Andrew J Brenner 3 11,  Vijaya Manthati 4,  Manjeet K Rao 3 12,  Rajeshwar R Tekmal 1 3,  Hareesh B Nair 13,  Klaus J Nickisch 4,  Ratna K Vadlamudi 14 3
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
  • 2 Department of General Surgery, Xiangya Hospital, Hunan, China.
  • 3 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
  • 4 Evestra, Inc., San Antonio, Texas.
  • 5 Department of Gastroenterology, Second Xiangya Hospital, Hunan, China.
  • 6 Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China.
  • 7 UT Southwestern Medical Center, Dallas, Texas.
  • 8 Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
  • 9 Cedars-Sinai Medical Center, Los Angeles, California.
  • 10 Jagiellonian University Medical College, Krakow, Poland.
  • 11 Hematology & Oncology, University of Texas Health San Antonio, San Antonio, Texas.
  • 12 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
  • 13 Evestra, Inc., San Antonio, Texas. [email protected] [email protected].
  • 14 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas. [email protected] [email protected].
PMID: 31142661 DOI: 10.1158/1535-7163.MCT-18-1258
Abstract

Leukemia Inhibitory Factor receptor (LIFR) and its ligand LIF play a critical role in Cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes Apoptosis in triple-negative breast Cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and Akt. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patient-derived primary TNBC explants. EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling.See related commentary by Shi et al., p. 1337.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120142
    98.11%, LIFR Inhibitor