The focus of Elgendy’s research lab is medicinal chemistry with a broad goal of drug design and optimization. We use rational drug design approaches to develop small molecule drug candidates for some of the most challenging diseases such as fatty liver diseases, atherosclerosis, Alzheimer’s disease, cancer, Zika virus, and hepatitis C virus (HCV).
Major Areas of Research Interest:
Liver X receptors (LXRs) are promising drug targets because they play paramount role in many physiological processes and regulate inflammation and immunity in many cell types. Development of new LXR modulators can help in finding treatment for many challenging diseases. We are particularly interested in increasing the understanding of the mechanisms by which liver X receptors (LXRs) signaling regulates lipid homeostasis in different tissues (including the liver, intestine and brain). Our work has highlighted new opportunities for therapeutic intervention in human metabolism by introducing new strategies for the pharmacological manipulation of LXRs and their target genes and offer promise for the treatment of human diseases in which lipids have a central role, including liver diseases, cancer, type 2 diabetes, atherosclerosis and Alzheimer's disease. Moreover, liver X receptor (LXR) is a potential drug target for the treatment of pain and their anti-inflammatory role has been established. For example, the transcription of genes encoding iNOS and COX-2 was inhibited by LXR agonists through inhibition of NF- κB. Furthermore, activation of LXRs with synthetic ligands was shown to alleviate pain in a rat osteoarthritis model by blocking prostaglandin E2 (PGE2) production. In arthritis, PGE2 increase the sensitivity of nociceptive neurons and contribute to the chronic pain of this disease. During inflammation, COX-2 is one of the main enzymes in PGE2 synthesis, and LXR ligands inhibit cytokine-induced expression of COX-2. Consequently, PGE2 production is blocked.
Currently, we are exploring the use of LXR modulators in the treatment of atherosclerosis, Alzheimer’s disease, and pain related diseases.
REV-ERBs are other nuclear receptors that were identified as orphan NRs in the early 1990s. Recently, the natural ligand, heme, was identified independently by the Burris lab and the Lazar lab. Both REV-ERBα and –β are constitutive repressors and this process is dependent on the presence of heme. The first synthetic agonist, GSK4112, was described in 2008 and demonstrated modulation of circadian function in tissue culture. We have designed and synthesized REV-ERB modulators that can directly modulate the activity of these receptors and can directly modulate the endogenous circadian rhythm and have the potential to treat diseases associated with clock dysfunction such as sleep disorders and anxiety. Our work in this area shows that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat not only sleep disorders and anxiety, but also other diseases such as muscle injuries and Alzheimer’s disease.
Estrogen Related Receptors (ERRs) are members of the nuclear hormone receptors (NRs) superfamily. ERRs are ligand-activated transcription factors and the ligands of NRs tend to activate or repress the transcription factors that control several genes involved in many important physiological processes such as metabolism, immunity, inflammation, homeostasis, development, cell growth, and reproduction. ERRα is known to be highly intractable as a drug target. The progress in drug development for ERRα is limited to the development of inverse agonists. We have identified ERRα selective agonists and we are developing these agonists to be used as chemical probes to validate ERRα as a putative target for the treatment of Alzheimer’s Disease.
We Synthesize complex and diverse molecules to combat multi-drug resistance bacteria, HCV, ZIKV, and other microbes. We incorporate computational methods such as quantitative structure activity relationships, pharmacophore modeling, and virtual screening in our drug discovery pipeline to accelerate the process of drug discovery and optimization.
We are developing a promising strategy for cancer treatment by targeting the Liver X receptors. Liver X receptors have multiple roles in cancer biology and can suppress the proliferation of a variety of human cancer cells by targeting the cell cycle at several points. We are developing new anticancer drugs that can spare healthy cells and avoid the toxicity and weight loss associated with chemotherapy. The new drugs will metabolically reprogram the rapidly growing cancer cells to ‘‘normal’’ metabolic cells that cannot sustain cancer cell growth, and this triggers apoptosis of the cancer cells.
Moreover, we designed and synthesized novel small molecules that can inhibit MDM2-p53 interaction for the treatment of cancer. Inhibiting p53 binding to MDM2 is a promising approach to cancer treatment. We have evaluated the anticancer activity of our scaffolds in vitro against multiple cell lines and synthesis of more scaffolds is underway.