Awuah, Samuel G

Introduction:
Samuel G. Awuah
Project Summary

Recent research efforts at the interface of chemistry and biology have advanced biomedical research and drug discovery. Our research program will focus on building on this innovation through the chemical synthesis of organic and the highly unexplored inorganic small molecule probes to interrogate human biology and develop new medicines. A creative combination chemical synthesis, computer aided drug design and molecular biology will lead to smart small molecule modulators of human biological processes and health to identify and validate drug targets, investigate drug resistance and develop effective small molecule therapeutics. Furthermore, we seek to investigate disease areas such as cancer, immune disorders, and infectious diseases. In the area of synthesis, there will be three major themes: i) genetic interactors and imaging tagged small molecule probes, ii) epigenetic drug discovery, iii) organometallic chemical genetics and iii) nucleolar-localizing therapeutics. Our drug discovery efforts of theme (ii) would lead us to uncover cancer epigenetic targets. Subsequently, small molecule inhibitors will be designed towards the drivers of “onco-epigenetics”. An interesting paradigm of research to be pursued is the sensing and inhibition of discriminative species that regulate T-cell recruitment in the tumor microenvironment (TME). T-cell infiltration is known to enhance vaccine efficacy and adoptive cell transfer in personalized immunotherapy for human cancer. The ability to detect trigger-molecules like reactive nitrogen species and the inhibition of their target chemokines would be my focus. In addition, our research team will seek to answer the question about nucleolus drug targeting - what is the functional role of RNA polymerase I and III in nucleolar disintegration and can we rationally design drug candidates for the nucleolus?

The following are projects to be undertaken in our laboratory:

1. Next Generation Small Molecule Epigenetic Chemical Probes – for elucidating biological processes underling epigenetic activity and implications for cancer drug discovery
2. Organometallic inspired chemical genetics – for uncovering disease targets of organometallics to aid rational design and to launch an organometallic based probe library program
3. Chemical-based immunotherapy and diagnosis for personalized medicine – for the development of detection agents for immune-biomarkers and attendant therapeutics for personalized medicine in cancer immunotherapy
4. Nucleolus mapping and targeting – for deeper understanding of the nucleolus and organelle specific drug discovery

The proposed chemical biology themes are emerging and have implications for complex human biology processes, drug discovery and medicine. When successful the university will own legal and intellectual properties to this research.

Targeting RNA Polymerase I to Induce Nucleolar Stress in MYC-Driven Breast Cancer

Work proposed for the period will be at the cutting edge of organic synthesis, chemical biology, and drug discovery to target MYC-driven breast cancers. The rapid discovery of small molecules that target promoters or binding cavities of RNA polymerase I will be a unique approach to dysregulate gene expression thereby stalling rDNA transcription activated by MYC hyperactivity. Our high throughput screening, validation and synthetic methodology for preparing RNA Pol I binding drug candidates represent an innovation that is expected to find use not only in our group but others, owing to its simplicity, robust nature, and reliability. Recent X-ray crystallographic information about a yeast homologue of RNA Pol I reveals among other differences a 10Å wider DNA-binding cleft than the other conserved RNA polymerases. Given that RNA Pol I is modulated by the MYC transcriptional program, this will enable us to formulate a rational design of small molecule anticancer drug candidates.

Software:

Tripos SYBYL docking software; Autodock4 AutoVina

Student

Xiao Tan
Jong Hyun Kim, Visiting Scholar

Sailajah Gukathasan, Grad Student, Chemistry

Amanda N Shaw, Undergrad, Chemistry

Sagar Gyawali, Student Teaching Assistant, Added to LCC on 01/05/2022

Jovita O Daraezinwa, Student Teaching Assistant, Added to LCC on 2/28/2022 

Udara T Munugoda Hewage, Graduate, Added on MCC, 06/25/2023 

Charles E Greif, Graduate, Added on MCC, 06/25/2023 

Developing small molecule immune modulators

Cancer is a major cause of death around the world as such several therapeutics are being developed to curb its effects and to kill cancerous cells. One of the most effective ways of fighting against cancer is immune-oncological strategies via checkpoint inhibition. This leads to a boost in the immune system’s identification and killing of cancerous cells. The overall goal of my research is to develop selective ‘context-driven’ small molecules that can be used as synthetic probes to elucidate the relationship between DNA repair mechanisms and immune checkpoint blockade.

Software:

Tripos SYBYL docking software; Autodock4 AutoVina

Student

Samuel Ofori
Jong Hyun Kim, Visiting Scholar

Randall T Mertens

Publications

2016 - 2019

1. Gukathasan, S.; Parkin, S.; Awuah, S. G. “Cyclometalated Gold(III) Complexes Bearing DACH Ligands”. Inorganic Chemistry 2019, 58, 149326-9340
2. Kim, J. H.; Mertens, R. T.; Agarwal, A.; Parkin, S.; Berger, G.; Awuah, S. G. “Direct intramolecular carbon(sp2)–nitrogen(sp2) reductive elimination from gold(iii)”. Dalton Trans. 2019, 48, 6273-6282
3. Mertens, R. T., Kim, J. H., Jennings, W. C., Parkin, S., Awuah, S. G. “Revisiting the reactivity of tetrachloroauric acid with N,N-bidentate ligands: structural and spectroscopic insights”. Dalton Trans 2019, 48, 2093-2099

Grants