Martin Safo, Ph.D.linkedin
Martin Safo research interest centers on rational structure-based design of drug candidates, as well as the development of novel protein structure and function studies.
Notably, for over 20 years, Safo has directed drug discovery programs to develop promising small molecules that target hemoglobin or pyruvate kinase for the treatment of sickle cell disease (SCD). Sickle cell disease is a hereditary blood disorder, affecting over 75,000 people in the United States and millions of people worldwide. The fundamental pathophysiology of SCD involves polymerization of sickle hemoglobin and the subsequent sickling of red blood cells, which occurs under conditions of low O2 saturation, i.e. when sickle hemoglobin is deoxygenated. A therapeutic strategy to prevent the polymerization and sickling is by using agents that bind to hemoglobin and increase the concentration of the non-polymer forming oxygenated sickle hemoglobin. Some of Safo’s earlier lead antisickling agents have been derivatives of the natural vanillin and 5-HMF, attractive food-based and non-toxic chemotypes. 5-HMF progressed through phase I/II clinical trials to treat SCD under the NIH Therapeutics for Rare and Neglected Diseases Program. Follow-up structure-based drug modifications of 5-HMF and vanillin have been ongoing, producing derivatives with significantly enhanced pharmacologic properties. Some of these compounds not only increase the concentration of the non-polymer forming sickle hemoglobin, but directly inhibit polymerization of sickle hemoglobin. One of the compounds VZHE-061 (ILX-002) is currently undergoing an IND-enabling studies for the treatment of SCD, and expected to undergo phase I clinical trials in humans in 2025.
Safo is also involved in studying small molecule modulators of liver pyruvate kinase (PKLR), as well as validating and targeting PKLR for treating cancer or sickle cell disease. He has identified several lead pyruvate kinase modulators, including compounds that have potential for treating cancer or sickle cell disease, and for the former compounds that potently suppress hepatocellular carcinoma (HCC) cell growth.
Another exciting but challenging area of Safo's research focuses on the homeostasis of the biologically active form of vitamin B6, pyridoxal 5’-phopshate (PLP). PLP is a cofactor for over 180 PLP-dependent enzymes, serving a vital role in numerous essential pathways, e.g. amino acid metabolism, carbohydrate metabolism, neurotransmitter biosynthesis. Mammals rely on a salvage pathway, involving pyridoxal kinase, pyridoxine 5’-phosphate oxidase, pyridoxal reductase, and phosphatases to synthesize PLP and/or recover B6 during enzyme degradation. Disruption of the salvage pathway, e.g. through pathogenic mutations or inhibition of the salvage enzymes, leads to severe deficiency of PLP, and, consequently, sluggish activity of PLP-dependent enzymes, which contribute to pathologies, e.g. convulsions, neonatal epileptic encephalopathy, etc. Safo work involves elucidating the role of the vitamin B6 salvage pathway in preventing toxic buildup of PLP and/or other B6 vitamers, while at the same time supplying sufficient PLP for dozens of newly synthesized apo PLP-dependent enzymes to form catalytically active holo-enzymes.