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
  • 1. Discovery Chemistry, Princeton, NJ 08543, United States. Electronic address: [email protected].
  • 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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