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The Baylor Synthesis and Drug-Lead Discovery Lab is a collaboration center with synthetic organic/medicinal chemistry expertise serving as an interface between bioactive small molecule/natural product identification and cell biology/mode of action studies for drug discovery. We would be interested in future collaborations, including grant proposals, if you need synthetic organic chemistry or reaction screening and optimization support for one of your projects. Please contact us:
Email: john_L_wood@baylor.edu | daniel_romo@baylor.edu | Kenneth_hull@baylor.edu
Phone: (254) 710-2162
CURRENT COLLABORATORS | PAST COLLABORATORS
David Horgen (Hawaii Pacific University), Andrea Fleig (The Queen’s Medical Center, Hawaii) and Hong-Shuo Sun & Zhong-Ping Feng (University of Toronto)
“Development of the waixenicin A pharmacophore as a therapeutic intervention for neonatal hypoxic brain injury”
Neonatal and perinatal hypoxic-ischemic brain injury (HIBI) is a major cause of acute mortality and chronic neurological morbidity in infants and children occurring in 2% of full-term infants and approaches 60% in premature infants. 20% to 50% of asphyxiated newborns die. Among the survivors, up to 25% show permanent neuropsychological handicaps such as cerebral palsy, generating lifetime costs to the US healthcare system at an estimated $11.5 billion USD. Therapeutic hypothermia was the first evidence-based neuroprotective therapy for neonates with hypoxic-ischemic encephalopathy (HIE) and has become the clinical standard of care (SOC). Despite reducing the combined rate of death and disability, therapeutic hypothermia has to be initaited within 6 hours of HIE, a very narrow diagnostic window. Neonates diagnosed within this time frame are treated with hypothermia for 3 days. Currently about half of hypothermia-treated HIE neonates experience adverse outcomes with personal and socioeconomic implications. Clearly, there is an unmet need for adequate therapeutic interventions against HIBI beyond current SOC. The divalent ion channel-kinase fusion protein TRPM7 controls critical cellular processes involved in ischemic events, including experimental HIBI, and is a biologically logical and highly promising target for drug development, particularly in light of the discovery of a highly selective and potent inhibitor, waixenicin A (WaixA). This provides an excellent starting point to develop semi-synthetic derivatives of WaixA with improved pharmacological properties towards therapeutic intervention in HIBI.
Due to the established involvement of TRPM7 in hypoxia and WaixA effectiveness in HIBI, we hypothesize that semi-synthetic waixA derivatives protect against HIBI; that semi-synthetic analogs of WaixA covalently bind to TRPM7; and that, based on its excellent predicted blood-brain-barrier properties, optimized semi-synthetic analogs of waixA with improved physiochemical properties can serve as therapeutic leads against HIBI.
Susan E. Bates (Columbia University Cancer Center)
“Exploiting a Metabolic Vulnerability Created by Epigenetic Therapy”
Pancreatic cancer (ductal adenocarcinoma) is characterized by cancer-inducing, activating KRAS mutations that support the growth and survival of a tumor with one of the fastest growth rates among human solid tumors. Among the functions of mutant KRAS is inducing reprogrammed metabolism, the breakdown of nutrients for energy, via several downstream pathways.
Dr. Bates and her team have identified a strategy that interferes with the high metabolic need of pancreatic cancer cells by systematically depleting essential nutrients from the cancer cells. The goal is starvation of nutrients that will lead to cancer cell death. This strategy is based on the interaction of two drugs that work together to lethally interfere with cellular metabolism. Early experiments have suggested that the drugs are synergistic, which means their combined effect is stronger than adding each individual drug’s effect together.
The two drugs being utilized are a histone deacetylation inhibitor (Romidepsin) and a protein translation inhibitor (Des-Methyl Pateamine A, DMPatA). Blocking histone deacetylation results in global hyperacetylation that is thought to limit cell growth or induce cell death. The protein translation inhibitor will reduce levels of a protein called MYC with cancer-causing activities. We are providing DMPatA to Dr. Bates’ lab for the two drug combination studies and the Baylor Synthesis and Drug-Lead discovery Lab, in collaboration with the Baylor MiniPhrama undergraduate team, is also preparing new derivatives of pateamine A for evaluation versus pancreatic cancer.
Ryuichi Sakai (Hokkaido University, Japan) and Sarin Chimnaronk (Mahidol University, Thailand)
“An international platform for discovery of novel chemotypes against Flaviviruses” and “Development of novel, broad antiviral drugs by targeting the human ribosome”
Flaviviruses include many of the most prevalent human pathogens such as dengue virus (DENV), West Nile virus (WNV), Zika virus (ZIKV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV). DENV alone accounts for nearly 400 million infections and 500,000 hospitalization per year worldwide. Currently, there is no effective drug or vaccine against DENV and ZIKV, and it has been shown that DENV can cross-react with ZIKV to enhance disease severity in endemic areas. To develop a new antiviral drug candidate, a significant iterative experimental process including target identification, screening, and chemical modification is required and this multidisciplinary research is difficult to conduct effectively in developing countries. The project’s goal is to internationally connect academic researchers to establish a unique platform for drug lead discovery to tackle the problem of tropical infectious diseases. The team will employ an in vitro high-throughput screening system developed in Dr. Chimnaronk’s group, to test inhibitory effects on the RNA-binding capacity of viral NS5 RNA polymerase, an essential enzyme in DENV and ZIKV required for replication. It will screen marine-derived bioactive substances because historically marine extracts have been proven to be a good source for drug lead discovery from Dr. Sakai’s well characterized marine natural products library. Finally, chemical synthesis and derivatization of the natural products will be led by Dr. Romo. The team is also seeking additional funding to support the development of Agelastatin A, a protein synthesis inhibitor, as an antiviral agent.
Zhiqiang An and Kyoji Tsuchikama (The University of Texas, Health Science Center at Houston)
“Novel antibody drug conjugates using protein synthesis inhibitors and branched linker technology”
Antibody drug conjugates (ADCs) are a novel targeted drug development strategy in which an antibody is linked with a potent small molecule agent (warhead) to treat cancer. This emerging class of chemotherapy agents is being studied in this collaboration. Dr. Tsuchikama has developed new branched ADC linkers that can be equipped with multiple drug molecules (warheads). To date, most research in ADCs has focused on single warheads and this exciting new approach has the potential to be more effective at treating human disease. In this collaboration, protein synthesis inhibitors developed in our laboratory will be used in combination with Dr. Tsuchikama’s branched linker ADC technology.
Ali Al Mourabit (Institut de Chimie des Substances Naturelles, ICSN Paris, France), Shintaro Iwasaki and Tilman Schneider-Poetsch (RIKEN Center for Sustainable Resource Science, Japan) and Jun Liu (Johns Hopkins University, USA)
“Derivatization of Girolline for SAR studies”
Girolline (RP 49532A) is a protein-synthesis inhibitor isolated from a marine sponge that exhibits significant cytotoxicity in vitro against several cancer cell lines and antitumor activity in vivo against murine grafted tumors including P388, L1210 leukemias, and solid tumors. Studies indicated that girolline binds near the E site region of the 50S ribosomal subunit of haloarcula marismortui and likely inhibits tRNA binding by interfering with conformational changes that occur at the E site of the 50S ribosome. In addition, girolline also exhibits strong antimalarial activity against four Plasmodium falciparum strains with IC50‘s ranging from 77 to 215 nM. The investigation into the mechanism of action of girolline during the erythrocytic life cycle of the parasite suggested that its action targets the synthesis of proteins by the parasite. Such biological profile of girolline makes it a model chemical structure for new candidates in the arsenal of new drugs against cancer and malaria. Our contribution to this collaboration is to make new girolline analogs for SAR studies and structural modification heading to the new drug lead discovery.