Eric J Miller

• Doctor of Philosophy
• Researcher at Emory University

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel...

CXCR4 is a 7-transmembrane receptor expressed by hematopoietic stem cells and progeny, as well as by ≥ 48 different cancers types. CXCL12, the only chemokine ligand of CXCR4, is secreted within the tumor microenvironment, providing sanctuary for CXCR4+ tumor cells from immune surveillance and chemotherapeutic elimination by 1) stimulating pro-survi...

The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that antagonist-mediated, glutamate-independent inverse-agonism of group II and III mGlu receptors results from inhibition of chloride-mediated activation. In silico molecu...

A structure–activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener 15a was found to be a potent CXCR4 inhibitor (IC50 = 33 nM in CXCL12-mediated Ca²⁺ flux) with enhanced stability in liver microsomes a...

CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison to normal cells, cancer cells over-express CXCR4, which correlates with cancer cell metastasis, angiogenesis and tumor growth. CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12-mediated pro-...

5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic eve...

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside...

Purpose: Pro-angiogenic and immune cells expressing chemokine receptor CXCR4 traffic along concentration gradients of the chemokine ligand CXCL12, which disseminates from stromal niches. The CXCR4/CXCL12 axis is hijacked by various cancer types characterized by dramatic CXCR4 and/or CXCL12 upregulation. This chemokine network misregulation causes h...

Introduction: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of many human diseases. The FDA approval of the first CXCR4 antagonist drug Plerixafor (i.e., AMD3100, Mozobil®) ushered in an increase in patent activity covering CXCR4 based therapeutic agents over...

CXCR4 is a G protein-coupled receptor that interacts with its cognate ligand CXCL12 to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the d...

A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 (5) in a SDF-1 induced calcium flux assay. Preliminary SAR investigations led us to identify a series containing N-propyl pip...

NMDA receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically-relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NM...

Group II and group III metabotropic glutamate (mGlu) receptors are G protein-coupled receptors (GPCRs) that inhibit adenylyl cyclase via activation of Gαi/o. The purpose of this study was to design a universal method that overcomes previous challenges in consistently measuring group II and group III mGlu receptor activation in stably transfected sy...

The metabotropic glutamate 1a (mGlu1a) receptor is a G protein-coupled receptor linked with phosphoinositide (PI) hydrolysis and with β-arrestin-1-mediated sustained extracellular signal-regulated kinase (ERK) phosphorylation and cytoprotective signaling. Previously, we reported the existence of ligand bias at this receptor, inasmuch as glutamate i...