title: Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models.
abstract: Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana. Peng_sheng-bin@lilly.com.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Donald
authors.initials: D
authors.lastname: Paul
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kays
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Wendy
authors.initials: W
authors.lastname: Gough
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Julie
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Uhlik
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hui
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: John A
authors.initials: JA
authors.lastname: Wijsman
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Credille
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
authors.forename: Liang Zeng
authors.initials: LZ
authors.lastname: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12; D004195:Disease Models, Animal; D004285:Dogs; D004355:Drug Stability; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; C000595455:LY2510924; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4