The research programs in Professor Shudong Wang’s group are directed towards the discovery and development of new drugs cancer therapies. . This involves multidisciplinary approaches where structure-guided and target driven methods are employed in an effort to identify drug candidates and novel therapeutic targets. The blend of extensive capabilities in cutting-edge computational drug design, medicinal chemistry, cellular and animal pharmacology, and toxicology in the single cohesive research centre holds the promise for rapid advancement of drug discovery and development. Below are details on some of these research projects:
Identification of Mnk inhibitors using structure-based approaches
MAPK-interacting kinases (Mnks) are responsible for many types of human cancers and their inhibition provides an effective anti-cancer strategy (Chem. Biol. 2014, 21, 441-52). In this project, we are designing and synthesising libraries of heterocyclic compounds that block Mnk activity by targeting the ATP binding site. We have developed biochemical assays to determine compounds’ potency, specificity and mechanism(s) of binding. We have also employed cutting-edge in silico methods and crystallography to understand modes of inhibitor binding and structure-activity relationships. The outcomes of this project will significantly advance the current understanding of the structure and mechanisms underpinning Mnk activity. These inhibitors will be invaluable chemical and biological tools to study the role of Mnk in protein translation leading to its pharmacological target validation.
Pharmacological inhibitors of CDK4/6 for treatment of cancer
Cyclin D dependent kinases CDK4 and CDK6 play a vital role in cell cycle progression, but also maintain important functions in carcinogenesis due to their deregulation (Cell Cycle 2015, 14, 3220-30). As > 90% of tumours show aberrance in CDK4/6 cyclin D-INK4-pRb-E2F pathway, the discovery and development of selective small molecule inhibitors would be highly valuable in treating cancers. In the CDK4/6 cyclin D-INK4-pRb-E2F pathway, CDK4/6 exert their functionality via phosphorylation of the retinoblastoma protein (pRb). Once phosphorylated, pRb loses its inhibitory effect on the transcription of genes promoting entry into S phase of the cell cycle. Hence, CDK4/6 inhibition results in hypophosphorylated pRb and arrest cell cycle at the G1 R point. In the CDK4/6 project we are discovering and developing potent and selective CDK4/6 inhibitors with favourable pharmacokinetic properties for the treatment of cancer.
Discovery of highly selective CDK9 inhibitors for therapy
Cyclin-dependent kinase 9 (CDK9) and cyclin T or cyclin K constitute the positive transcription elongation factor b (P-TEFb), a well-validated target for the treatment of several diseases including cancer. Several anti-cancer drug candidates have been clinically evaluated as CDK9 inhibitors. Regrettably, these molecules lack selectivity for CDK9, leading to major off target effects and hampering their potential clinical use. Hence, there is a pressing demand to discover highly selective CDK9 inhibitors. We have recently designed and synthesised a few prototype molecules that selectively inhibit CDK9 among several CDKs (J. Med. Chem. 2013, 56, 640-59), and rationalised their selectivity over CDK2 (J. Med. Chem. 2013, 56, 660-70). We are currently tailoring the scaffold of these molecules to achieve even higher selectivity over a broader range of kinases. We also combined available CDK2/9 crystallographic data with in silico modelling in a novel approach, to design potential allosteric inhibitors to target a little known allosteric binding site of CDK9, exploiting structural dissimilarities among kinases outside the traditionally targeted ATP-binding pocket. We expect our highly selective CDK9 inhibitors will offer effective anti-cancer treatments with minimal side-effects.
Pre-clinical development of mitotic inhibitors as anti-cancer agents
Targeted cancer therapeutical agents have the advantage of reduced side effects; however, the genetic instability of cancer allows mutations to occur, developing resistance to these therapies. Targeting the key components of signalling pathways that are critical for cancer cell survival has been proposed as a more effective anti-cancer strategy, particularly for the treatment of advanced stages. We have developed a novel class of small molecule heterocyclic compounds that showed high potencies against a panel of human cancer cells lines. The lead compounds target the cellular key regulators of mitotic pathways of the cell cycle and effectively induce cancer cell apoptosis. Importantly, the lead compounds demonstrate the favourable drug-like properties, including high oral bioavailability. This project aims to evaluate pre-clinical anti-tumour efficacy and toxicity of these compounds to facilitate potential clinical studies.
Targeting CDK8 for treatment of colorectal cancer
The Wnt/β-catenin signalling pathway is frequently down-regulated in most colorectal cancers. Cyclin dependent kinase 8 (CDK8) has been identified to have both direct and indirect roles in regulating the β-catenin-driven oncogenic transformation. Therefore, inhibiting CDK8 in such cancer may be of appealing clinical value. In fact, it has been shown that colon cancer cell proliferation is suppressed by depleting CDK8 expression in cell lines with high levels of CDK8. The goal of this project is to discover and develop novel, highly selective and potent CDK8 inhibitors that would be effective candidates for clinical drug development.
The project was initiated with a high throughput in silico screen of a large in-house library of compounds to identify potential hits and novel structural scaffolds. Medicinal chemistry routes to synthesise and establish structure-activity relationships have been developed. Biochemical and cell-based assays to evaluate inhibitory activities of the compounds against CDK8 and the Wnt/β-catenin pathway are being developed. This project aims to identify CDK8 inhibitor drug candidates that can be developed towards the clinic.