Suto Lab

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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, acute kidney injury, and amyotrophic lateral sclerosis (ALS).

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

https://www.lls.org/

 

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

Mark J. Suto, Ph.D.

Vice President, Drug Discovery

Mark J. Suto, Ph.D., was named vice president of Drug Discovery in August 2011. He and his team focus on basic research and target identification and lead discovery and optimization of new therapies for cancer, infectious diseases, and neurological diseases and disorders.

[ Read Full Bio Here ]

Lab Members

Vandana V. Gupta, Ph.D.,

Vandana V. Gupta, Ph.D.,

Researcher

Vandana V. Gupta, Ph.D., 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, Dr. Gupta later joined GVK Bio, a contract research organization (CRO) company, based in Hyderabad, India in 2009 as Senior Research Associate where she gained two years of industrial experience. She then joined Southern Research as a Post-Doctoral Research Fellow in 2012, and after three years, was promoted to Associate Research Chemist. At Southern Research, Dr. Gupta has been involved in LRRK2 Drug Discovery program, synthesizing small molecule inhibitors as a potential therapeutic for the treatment of Parkinson’s disease and more recently 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 support Dr. 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.

Jordan Entrekin, Ph.D.,

Jordan Entrekin, Ph.D.,

Researcher

Jordan Entrekin, Ph.D., received his Bachelor’s of Science in 2010 and his Doctorate in 2016 from the University of Alabama. Immediately following, he joined the Department of Chemistry, Drug Discovery Division at Southern Research as a Post-Doctoral Research Fellow.
As an undergraduate, Dr. Entrekin combined his interests in science and medicine with his passion for puzzles and problem-solving by pursuing a degree in chemistry. He initially participated in organometallic research as an undergraduate, and later broadened his experiences to focus on synthetic methodology. As a graduate student, Dr. Entrekin studied the development of methodology for the preparation of C-glycosides which are valuable structural motifs in many biologically active natural products and several important prescription drugs. At Southern Research, Dr. Entrekin intends to leverage his background in synthetic methodology and reaction optimization to develop concise and economical routes to biologically-relevant compounds of interest, such as compounds for the treatment of NF-kB activation for the treatment of ALS, and for TSP-1 mediated TGF-β activation for potential treatment of Multiple Myeloma.

Shilpa Dutta, Ph.D.,

Shilpa Dutta, Ph.D.,

Researcher

Shilpa Dutta, Ph.D., received her Master’s in Chemistry with Honors from Panjab University, India and Doctorate from the University of Alabama at Birmingham (UAB) under the mentorship of Drs. Wayne J. Brouillette and Sadanandan E. Velu. Dr. Dutta’s doctorate research 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. Dr. Dutta joined Southern Research in August 2016 as a Post-Doctoral 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.

Bini Mathew, Ph.D.,

Bini Mathew, Ph.D.,

Researcher

Bini Mathew, Ph.D., received her Doctorate in Organic Chemistry from Mahatma Gandhi University by working at the National Institute for Interdisciplinary Science & Technology, a premier research institute under the Council of Scientific and Industrial Research (CSIR) of Ministry of Science and Technology, Government of India. Subsequently in 2002, Dr. Mathew began a two-year Post-Doctoral Fellowship at the University of Konstanz, Germany, as an Alexander von Humboldt Fellow, under the mentorship of Prof. Richard R. Schmidt, followed by a one-year Post-Doctoral Fellowship at Ohio State University under the mentorship of Prof. Robert C. Coleman. Following her post-doctoral training, she has since gained more than 14 years of research experience in the areas of 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, with ten of those years spent more recently at Southern Research, in which her current role focuses on structure-based drug discovery at Southern Research for cancer and infectious diseases. Dr. Mathew has authored several peer-reviewed publications in journals such as Nature Immunology and Journal of Clinical Investigation, and is an inventor on several patents. She has been the recipient of the Excellence Award from Southern Research in 2010 and 2015. Currently, Dr. Mathew is working on various collaborative projects between Southern Research and the University of Alabama at Birmingham (UAB) 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.

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


How To Work With Us

 

Southern Research welcomes collaboration opportunities with both academic and industrial research partners.