Design and Synthesis of Small Molecule Compounds for the Treatment of Resistant Cancers:
Cancer cells can adapt and develop resistance to chemotherapy drugs, making it difficult to eradicate tumors. Preventing or delaying the emergence of drug resistance is likely to enhance the effectiveness of chemotherapy and improve clinical outcomes for patients with cancer. Research in our lab mainly focuses on the development of small molecule anticancer agents for the treatment of resistant cancers. As a PI or co-Investigator on LA-Board of Regents and LBRN(NIH-INBRE) funded grants, I laid the foundation for the development of molecular hybrids as potential anticancer agents. I have collaborated with the experts in the fields of pharmacology and bioinformatics to study insilico, in vitro and in vivo anticancer activities, and related mechanistic aspects. The design and synthesis of molecular hybrids and their anticancer activity studies is the main goal of the research program. Our research involves two major areas of research, 1) Design, synthesis, and anticancer activity evaluation of small molecules to identify the most potent, selective and drug-like hit/lead compound(s). 2) Study the mechanism of action of our hit/lead molecules to identify the most affected pathways and the related biological target(s).
1. Design, synthesis, and evaluation of pyrazole-based molecular hybrids as potential anticancer agents.
PI’s lab designs and synthesizes novel libraries of small molecules and uses phenotypic screening approaches to evaluate them for antiproliferative activity. Over the past six years, the group has designed and developed several small molecule compounds that function as potent anti-proliferative agents against types of lung and skin cancer cell lines. We have been developing pyrazole-based molecular hybrids, by the inculcation of active pyrazole pharmacophore with privileged heterocyclic scaffolds, that could possibly trigger two or more pharmacological mechanisms of action acting in synergy to inhibit tumor growth especially in drug-resistant cancers. The group currently focuses on hit-to-lead optimization of small molecules using insilico approaches, synthetic chemistry, and in vitro biological assays.
2. Target Deconvolution and Mechanism of Action Studies
Identifying the molecular targets of active hits from phenotypic screens is a crucial process that is required to understand underlying mechanism of action and to further optimize active compounds. Along those lines, we utilize proteomics and genomics-based approaches along with bioinformatic tools. With collaborative efforts, we have recently utilized kinase profiling, ProliFiler screening and RNA seq analysis to identify affected pathways and possible targets of our pyrazolone-based hit compounds and gathered very useful information for further development of compounds. Because of the complex nature of these advanced techniques, strong collaborations with different expertise can have a big impact on our ability to identify targets more rapidly and efficiently and to provide direct contributing links between a hit binding to its target and a phenotypic outcome.
Education: PhD
ORCID identifier: https://orcid.org/0000-0002-1956-3079
MyNCBI Link: https://www.ncbi.nlm.nih.gov/myncbi/siva.murru.1/bibliography/public/
Selected Publications:
1. Boateng ST, Roy T,Torrey K, Owunna U, Banang-Mbeumi S, Basnet D, Niedda E, Alexander AD, Hage DE, Atchimnaidu S, Nagalo BM, Aryal D, Findley A, Seeram NP, Efimova T, Sechi M,Hill RA, Ma H, Chamcheu JC, Murru S. Synthesis, in silico modelling, and in vitro biological evaluation of substituted pyrazole derivatives as potential anti-skin cancer, anti-tyrosinase, and antioxidant agents. J Enzyme Inhib Med Chem. 2023 Dec; 38(1):2205042. doi:10.1080/14756366.2023.2205042. PMID: 37184042; PMCID: PMC10187093.
2. Dahal A, Lo M, Singh S, Vo H, ElHageD, Jois SD, Murru S. 1,3-diarylpyrazolones as potential anticancer agents fornon-small cell lung cancer: Synthesis and antiproliferative activity evaluation. Chem Biol Drug Des. 2022 Apr;99(4):620-633. doi:10.1111/cbdd.14030. Epub 2022 Mar 1. PMID: 35156777; PMCID: PMC10127554.
3. Roy T, Boateng ST, Banang-Mbeumi S,Singh PK, Basnet P, Chamcheu RN, Ladu F, Chauvin I, Spiegelman VS, Hill RA,Kousoulas KG, Nagalo BM, Walker AL, Fotie J, Murru S, Sechi M, Chamcheu JC. Identification of new fisetin analogs as kinase inhibitors: Data on synthesis and anti-skin cancer activities evaluation. Data Brief. 2021 Apr; 35: 106858.doi: 10.1016/j.dib.2021.106858. eCollection 2021 Apr. PMID: 33665254; PMCID:PMC7907707.
4. Roy T, Boateng ST, Banang-Mbeumi S,Singh PK, Basnet P, Chamcheu RN, Ladu F, Chauvin I, Spiegelman VS, Hill RA,Kousoulas KG, Nagalo BM, Walker AL, Fotie J, Murru S, Sechi M, Chamcheu JC.Synthesis, inverse docking-assisted identification and in vitro biological characterization of Flavonol-based analogs of fisetin as c-Kit, CDK2 and mTORinhibitors against melanoma and non-melanoma skin cancers. Bioorg Chem. 2021Feb; 107:104595. doi: 10.1016/j.bioorg.2020.104595. Epub 2020 Dec 30. PMID:33450548; PMCID: PMC7870562.
Keywords/Tags: Small Molecules, Molecular Hybrids,Anticancer Agents, Target Identification
Link to lab website: https://webservices.ulm.edu/facultyactivities/profile/murru
