It is both the best and the worst time for computer-aided drug discovery. Big data combined with the state-of-the-art artificial intelligence (AI) can increase our capabilities, while pharmaceutical development faces severe economic pressure and high societal needs of improving drug hunting against challenging targets in all diseases.


Our work encompasses curation of big data, development of new algorithms, implementation of robust workflows, and their application to rational drug design and discovery. Over the years we have developed a variety of novel computational strategies such as ALL-QSAR, DOVIS and POLYPHARMA by integrating cheminformatics, bioinformatics, and systems chemical biology approaches. More recently as witnessed in the resurgence of AI, we are developing an utterly novel image-based AI platform (termed AI4MI) to predict direct molecular interactions including protein-protein, protein-RNA/DNA, and protein-small molecule interactions, which are key to molecular signaling, cell growth, and disease development. Such technologies are particularly invaluable when applied to an emerging field, for instance, protein-miRNA interactions, where very little information is available. Along the same line, we combined the large amount of cell line and patient genomic profiles and chemical compound structure-activity data to build AI models (termed DL4DR) that enables us to deep screen for drug responses in all cancer cell lines (>1,400). We expect that these technologies are game changers by minimizing, or even eliminating, the need of costly and time-consuming laboratory tests for molecular interactions or drug responses and provide more complete pictures of molecular signaling and disease-driving mechanisms.


We are especially interested in targeting those traditionally viewed undruggable molecular pathways. For instance, it has been revealed that S-phase kinase-associated protein 2 (Skp2) is overexpressed in many cancers and represents a molecular marker for poor prognosis. Moreover, Skp2 is a novel E3 ligase for Akt that triggers non-proteolytic K63-linked ubiquitination of oncogenic Akt, which facilitates Akt activation, leading to increased cancer glycolysis. In addition, Skp2 inactivation triggered a massive cellular senescence and/or apoptosis response in a p19Arf/p53-independent, but p27-dependent manner. Therefore, we developed first-in-class small molecule inhibitors which exhibit potent anti-tumor activities through specific Skp2 targeting (Cell 2013) as a promising "pro-senescence/apoptosis" and "anti-glycolysis" approach to cancer therapy. Currently we are conducting IND-enabling studies for regulatory filing and first-in-human trials. More recently, with our multi-modal approaches based on the latest AI technologies and chemo-genomic approaches, we have been very fruitful in polypharmacology studies and drug repurposing. One of the most success stories is discovery of a previously shelfed drug, poziotinib, as a potent and selective inhibitor of EGFR/HER2 exon-20 insertion mutants. In a further Phase 2 clinical trial, the drug shrunk tumors significantly in eight of 11 NSCLC patients (Nat Med 2018). With such exciting result, MD Anderson and Spectrum Pharmaceuticals signed a licensing agreement, and the Phase II clinical trial is being continued as one of the largest Phase II clinical trial in the world for this subset of NSCLC patient population. Our other high impact publications include (Nature 2019; Nat Commun 2019; Nat Commun 2018; Nat Cell Biol. 2017; Nat Commun 2017; JNCI 2012).


Entrepreneurially, we have filed more than 15 patent applications and intellectual disclosures to date. In 2009, we co-founded PHusis Therapeutics to translate our promising cancer therapies currently at the different stages of preclinical and clinical studies. We also co-founded TheraXen Technologies to further develop our PH domain-based technologies. These intensive experiences signify our resolve as scientific entrepreneurs to translate our laboratory discoveries to product commercialization and clinical patient treatment.


We have been supported by numerous funding agencies: