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 IC 50 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 IC 50 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. Mol Cancer Ther; 14(2); 480-90. Ó2014 AACR.

Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy

“…[8][9][10][11][12][13][14][15][16] LY2510924 is a novel and potent selective peptide antagonist of CXCR4. 17 A recent phase 1 study in advanced cancers revealed good tolerability with mostly grade 1 to 2 adverse events, favorable pharmacokinetics, and target engagement as indicated by dose-dependent increases in CD34 1 cell mobilization. 18 Here, we report preclinical studies using LY2510924 to disrupt the SDF-1a/CXCR4 axis in AML cells in vitro and in vivo.…”

A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies

“…Consistent with the protective role that this pathway plays, increased activity of this signaling axis is correlated with poor prognosis. 4,7,8,39,40 CXCR4 inhibitors currently being evaluated in the clinic, including small molecules, 23 peptides, 24,25 and an IgG4 Ab, [27][28][29][30] can mobilize tumor cells, sensitizing them to cell killing by chemotherapy. 17,41 PF-06747143, a novel humanized IgG1 Ab, binds to CXCR4 and potently inhibits CXCL12/CXCR4-mediated cell signaling pathways such as cAMP and cancer cell migration.…”

“…It is important to note that the ability of anti-CXCR4 agents to simply mobilize cells appears to be insufficient to drive antitumor activity. For instance, the CXCR4 peptide antagonists LY2510924 24 and BKT140/BL8040/TN14003 25 induce cell mobilization as monotherapies but failed to reduce tumor burden in clinical trials. 25,26 Interestingly, the CXCR4 partial agonist small molecule AMD3100 (Plerixafor; Mozobil), which induces mobilization of leukemic blasts from the BM, is undergoing clinical evaluation in hematologic malignancies in combination with chemotherapy, as a means to eliminate the mobilized cancer cells.…”

New agents in HSC mobilization

“…Unlike POL6326, the small molecule CXCR4 inhibitor TG-0054 (Burixafor) [29] and the cyclic peptide BKT-140 [30] have been tested with G-CSF and shown to synergistically augment HSC mobilization when given as a single dose after a standard course of G-CSF, results which were corroborated in human volunteers and patients with haematological malignancies [31][32][33][34]. Other promising CXCR4 antagonists in development for HSC mobilization include the cyclic peptide LY2510924 [35][36][37] and the small molecule ALT-1188 [38]. Notably, ALT-1188 has been shown to effectively mobilize murine HSPC when given as a single dose and synergistically when used in combination with G-CSF [38].…”