2. Academic Validation
  3. Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1)

Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1)

  • Bioorg Med Chem Lett. 2023 Dec 13:98:129589. doi: 10.1016/j.bmcl.2023.129589.
Jennifer X Qiao 1,  Mark R Witmer 2,  Ving Lee 3,  Tammy C Wang 3,  Patrick C Reid 4,  Yuki Arioka 4,  Glen Farr 5,  Melissa Hill-Drzewi 5,  Liang Schweizer 5,  Aaron Yamniuk 2,  Lin Cheng 2,  Bozena Abramczyk 2,  Martin Corbett 2,  Deepa Calambur 2,  Nicolas Szapiel 2,  Rolf Ryseck 2,  Paul Ponath 6,  Michael A Poss 3,  Percy Carter 3
Affiliations

Affiliations

  • 1 Discovery Chemistry, Princeton, NJ 08543, United States. Electronic address: jennifer.qiao@bms.com.
  • 2 Molecular Discovery Technology, Princeton, NJ 08543, United States.
  • 3 Discovery Chemistry, Princeton, NJ 08543, United States.
  • 4 PeptiDream 3-25-23 Tonomachi, Kawasaki-Ku, Kawasaki-Shi, Kanagawa 210-0821, Japan.
  • 5 Leads Discovery & Optimization, Princeton, NJ 08543, United States.
  • 6 Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, United States.
PMID: 38097140 DOI: 10.1016/j.bmcl.2023.129589
Abstract

Elevated levels of receptor tyrosine kinase-like Orphan Receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic Peptides as Binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle Peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic Peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these Peptides were not observed to induce Apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

Keywords

Extracellular CRD domain; Human receptor tyrosine kinase-like orphan receptor 1 (ROR1); Macrocyclic peptides; Peptide Drug Conjugate (PDC); Peptide synthesis and SAR; mRNA in vitro selection technology.

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