Research Focus

The Suto laboratory is involved with the identification and lead optimization of new therapeutics. The group currently has active medicinal chemistry programs to identify compounds for the treatment of multiple myeloma, glioblastoma, and acute kidney injury.

Major Research Programs

  • Inhibitors of Transforming Growth Factor (TGF)-β for Multiple Myeloma and Fibrotic Conditions

    Transforming growth factor (TGF)-β supports multiple myeloma progression and associated osteolytic bone disease as well as is associated with several fibrotic conditions. Conversion of latent TGF-β to its biologically active form is a major regulatory node controlling its activity. Thrombospondin1 (TSP1) binds and activates TGF-β and has been implicated in several disease processes.

    The Suto lab is collaborating with the Ulrich Lab at the University of Alabama at Birmingham to focus efforts on identifying antagonists of TGF-β activity. An antagonistic peptide for the latency-associated peptide region of TGF-β and binding site for TSP-1, LSKL, is the target of this work. We have identified several potent smaller tri-peptides (i.e. SRI31277) which have shown to be effective in mouse models of myeloma. In addition, we have now through a combination of computational studies and directed medicinal chemistry efforts identified several small molecule inhibitors of this pathway (Murphy-Ullrich JE et al. Am. J. Pathol. 2016; PMID 26801735)

    For grant support and additional information see:

    1R01CA175012-01A1             Project# 14351

    https://projectreporter.nih.gov/project_info_description.cfm?aid=8761464&icde=32480627

  • Hemeoxygenase-1 (HO-1) and Kidney Disease

    Acute kidney injury is a common and serious complication of medical and surgical diseases that has significant attributable morbidity and mortality, particularly in critically ill patients. Multiple epidemiological studies suggest a relationship of acute kidney injury with the subsequent development of chronic kidney disease. The goal of this project is to understand the protective mechanisms in the pathogenesis of acute kidney injury focusing on an anti-oxidant and anti-inflammatory protein, heme oxygenase-1 (HO-1). This is a multi-institutional collaborative project involving the laboratories of Anupam Agarwal (University of Alabama at Birmingham) and Suto (Southern Research), focusing on elucidating the biologic basis for the cytoprotective effects of HO-1, the molecular regulation of HO-1 gene expression, and generating relevant and feasible therapeutic strategies based on induction of HO-1 expression in acute kidney injury.

    The medicinal chemistry efforts are based upon hits from a high-throughput screen of >150,000 compounds that up regulate HO-1 levels. Current work is focused on identifying novel compounds that upregulate HO-1 levels in vitro, and with sufficient potency and bioavailability for in vivo evaluation in a model of kidney disease.

    For grant support and additional information see:

    https://projectreporter.nih.gov/project_info_description.cfm?aid=9037393&icde=32482452

  • Optimizing Small Molecule Inhibitors of Heparanase for Myeloma Therapy

    Myeloma is the second most common hematologic cancer. It thrives in the bone marrow and aggressively disseminates throughout the skeleton causing osteolysis, debilitating pain and devastating side effects. The tumors eventually become chemoresistant leading to patient death. The Suto Lab is collaborating with the Sanderson Lab at the University of Alabama at Birmingham to understand how heparanase promotes the aggressive behavior of myeloma and using that knowledge to develop curative therapies for myeloma patients. Multiple mechanisms through which heparanase drives myeloma progression and metastasis have been identified and heparanase as a viable target for myeloma therapy has been established. There is urgent need for small molecule inhibitors of heparanase that are homogeneous, highly specific and orally available.

    The goal is to develop small molecule inhibitors of heparanase drugs and demonstrate their efficacy against myeloma in vivo. The hits were identified through a virtual screen of using the published crystal structure of heparanase. The lab is working with several leads with the goals of optimizing potency and ADME properties to identify orally bioavailable inhibitors.

    For grant support and additional information see:

    Grant: 6518-17 | Translational Research Program (TRP):
    Leukemia Lymphoma Society

  • Development of Small Molecules Active at Disease Onset in ALS

    Amyotrophic lateral sclerosis (ALS) affects 1-2 humans every 100,000. The disease causes degeneration of motor neurons, paralysis and death. The disease is characterized by SOD1 abnormalities that results in an excess of reactive oxygen species (ROS) and mitochondrial sufferance. Transgenic animals carrying SOD1 mutations have been widely used to test experimental agents. We hypothesized that enhancement of MnSOD, spared by SOD1 failure could ameliorate the disease outcome. After a high throughput screening campaign, we identified two molecules which directly activate NF-kB p65 in brain cells via a non-cytokine receptor-mediated mechanism, and up-regulated MnSOD expression and activity in brain cells. These molecules have also shown neurotrophic and neuroprotective effects in vitro and active (IP) in a mouse model of ALS using SOD1-G93A animals. With disease onset, we saw a significant prolongation of life expectancy, decreased weight loss and improved neurologic symptoms. Current efforts have identified novel orally bioavailable compounds working through the same mechanism.

    For grant support and additional information see:

    https://www.mda.org/

    https://www.mda.org/sites/all/themes/mda_bootstrap_subtheme/pdf/ActiveGrantsAugust2016.pdf

Joint Appointments

  • UAB Center for Clinical and Translational Science, member
  • Senior Scientist, UAB Comprehensive Cancer Center, Experimental Therapeutics Program
  • UAB Adjunct Professor, Department of Chemistry

Meet Our Research Team

Mark J. Suto, Ph.D. | Vice President, Drug Discovery

Dr. Suto has over 35 years of industrial drug discovery and management experience serving in a range of capacities, from bench medicinal chemist to drug discovery program leader for major pharmaceutical companies. He has scientific and operational executive level experience in large pharmaceutical, biotech and not-for-profit research based organizations. He has managed programs that identified clinical candidates in several therapeutic areas, developed and managed research projects with large pharmaceutical partners, participated in due diligence exercises, and developed research strategies for collaborations. In 2016, Suto was inducted as a Fellow of the National Academy of Inventors in recognition of his wide-ranging contributions to pharmaceutical research and drug discovery efforts. He currently holds 45 U.S. patents and has four additional U.S. patents pending covering Composition of Matter and Use. He has more than 60 publications, and he has authored nine invited papers and book chapters. At Southern Research, he has overall responsibility for the research direction and strategy, scientific operations, talent, acquisition/development budgets, and P & L for the Drug Discovery division.

Shilpa Dutta, Ph.D. | Postdoctoral Research Fellow

Dutta received her doctorate from the University of Alabama at Birmingham under the mentorship of Drs. Wayne J. Brouillette and Sadanandan E. Velu.master’s, and her master's with honors in chemistry from Panjab University, India. Her doctorate research was centered on her passion to attain an in-depth understanding of preventing breast cancer metastasis, and a main focus of her work was developing small molecule blockers for voltage-gated sodium channels. Dutta joined Southern Research in 2016 as a postdoctoral research fellow. Her current research focus is on the prevention and treatment of myeloma, specifically on the identification and development of novel small molecule inhibitors of heparanase for myeloma therapy. Publications

Vandana V. Gupta, Ph.D. | Associate Research Chemist

Gupta completed her doctorate in organic chemistry in 2009 from the Central Drug Research Institute, Lucknow, India. Her graduate research experience includes the development of novel antibacterial and antihyperlipidemic analogs. Following graduate school in 2009, she joined GVK Bio, where she gained two years of industrial experience. In 2012, she joined Southern Research as a post-doctoral research fellow, and after three years, was promoted to associate research chemist. At SR, Gupta has been involved in the LRRK2 Drug Discovery program, synthesizing small molecule inhibitors as a potential therapeutic for the treatment of Parkinson’s disease. More recently, she has been focused on an NIH-funded Cancer program, TSP-1 mediated TGF-β activation for potential treatment of Multiple Myeloma. The main objectives for each of these projects are to design and synthesize novel molecules with superior potency, ADME and PK properties. Each of these programs supports Gupta’s current research interests, which lie at the interface of chemistry and biology, with a focus on the design and synthesis of novel molecules for the treatment of cancer and central nervous system disorders. Publications

Bini Mathew, Ph.D. | Research Chemist

Mathew received a doctorate in organic chemistry from Mahatma Gandhi University by working at the National Institute for Interdisciplinary Science & Technology. She completed a post-doctoral fellowship at the University of Konstanz, Germany, as an Alexander von Humboldt Fellow, followed by a post-doctoral fellowship at Ohio State University. She gained more than 14 years of research experience in medicinal chemistry, heterocyclic chemistry, carbohydrate chemistry, total synthesis of natural products, and discovery and lead optimization of small molecules for the development of novel drugs. Currently, she focuses on structure-based drug discovery for cancer and infectious diseases. Mathew has authored several peer-reviewed publications, and she is an inventor on several patents. She received the Southern Research Excellence Award in 2010 and 2015. Currently, Mathew is working on various collaborative projects between SR and the University of Alabama at Birmingham, such as Heme Oxygenase -1 Activation for Kidney Disease, NF-kB activation for the treatment of ALS, and TSP-1 mediated TGF-β activation for potential treatment of multiple myeloma. Publications