Fragment-Based Discovery of First-In-Class Small-Molecule Kinase Inhibitors for Targeted Cancer Therapies( I )( I )

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details


Background: Kinases have emerged as one of the most intensively studies protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents, due to their critical roles in cellular signaling. This project we aims at specifically our first-in-class small-molecule kinase inhibitors being explored lead optimization in current preclinical studies as anti-cancer drugs is a tendency to development. These pharmacological tools will thus be very helpful to detail the exact role of kinase in the phenomenon of tumoral therapy and resistance, and should lead to the proof-of-concept of the inhibition of these target enzymes in cancer therapy. Moreover this work should also constitute a strong basis for the design of new anticancer agents. Our strategy will include two specific approaches of drug discovery, namely a structure-based approach that will be focused on the optimization of a series tetracyclic azathioxanthone compounds that were recently shown to possess promising inhibition properties on both enzymes, and a second approach inspired from fragment-based drug discovery (FBDD), to discover novel inhibitors with inhibition profile. This strategy is thus highly multidisciplinary, involving a balanced combination of theoretical and experimental expertise’s such as organic chemistry, medicinal chemistry, physicochemistry, bioanalysis and biophysics. Purpose: The goal of this project is to optimize lead compounds of kinase inhibitors based on our patent small molecules to enhance their water solubility and also to evaluate the efficacy and safety of new lead compounds in cancer treatment. To improve the specificity of kinase inhibitors, we will generate a platform to measure the binding affinity of optimized lead compounds and evaluate the potency of lead optimization in vitro. The success of this project would lay the foundation for precision medicine to improve the treatment outcome of cancer by suppressing tumor progression. Method: Studies include the preparation of starting materials and FBDD, moreover the underlying mechanisms involved and SARs and their pharmacological activities are also investigated. Progresses of the studies are planned as: 1st year: Fragment-base design and lead optimization of tetracyclic azathioxanthone and identify their activity in cell based assays and NCI-60 assay. Effects of these potential compounds on alongside cytotoxicity tests with matched pairs of enzyme resistant, sensitive cells and cell lines are also investigated. 2nd year: To evaluate of these potential small molecules on DNA binding, enzymatic activities and kinase inhibition. To further evaluate these potential compounds in vitro, in vivo and animal studies. 3rd year: To study the effects of novel derivatives on DNA binding, relevant kinases and cytotoxicity. By comparing profiles of biological assay including the NCI-60 cell line assay, we will identify targets for small molecules development and lead optimization, which provide a rational basis for the SARs and pharmacological studies. Anticipated results: The study will lead to obtain potential target small molecules for development of more efficient and safer anti-cancer drugs.
Effective start/end date8/1/177/31/18


  • first-in-class
  • proof-of-concept
  • small-molecule kinase inhibitors
  • fragment-based drug discovery


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