AMD3465

AMD3465 is a **novel, monomacrocyclic small molecule antagonist of the chemokine receptor CXCR4**. It is a nonpeptide cyclam derivative designed to block the CXCR4 receptor, a G protein-coupled receptor involved in HIV viral entry and in cancer cell migration, invasion, and metastasis. Compared to the prototype CXCR4 antagonist AMD3100, AMD3465 exhibits higher affinity and potency for CXCR4, with 8–10-fold greater activity in inhibition and improved specificity (no measurable activity against CCR5, the other main HIV coreceptor)[1][3]. Mechanistically, AMD3465 inhibits the interaction of the CXCR4 receptor with its natural ligand (CXCL12/SDF-1), blocking downstream signaling events such as calcium mobilization, chemotaxis, and phosphorylation of key signaling proteins including STAT3, JAK2, AKT, ERK, and GSK3[1][3][5]. It demonstrates strong anti-HIV activity (inhibits entry of CXCR4-tropic HIV-1), and anti-tumor activity, including inhibition of tumor growth, metastasis, and the angiogenic process in preclinical models[4][5][6]. Additional studies show reduction of Treg and MDSC populations in tumors and modulation of the tumor microenvironment, supporting roles in immune modulation and possible combination immunotherapy settings[2][4][6]. Originally developed as an anti-HIV agent, AMD3465 has limitations in oral bioavailability, but represents an important scaffold in the search for orally active CXCR4 antagonists[1][3]. AMD3465 continues to be used as a tool molecule in oncology and HIV-related research to probe the role of CXCR4 in disease biology.

Other names

AMD3465AMD-3465AMD 3465