Image

Natural Product and AI-Guided Approaches to Novel Kinase Inhibitors

Kinase inhibitors are important as therapeutic drugs for targeted approaches to combating human diseases. The high structural similarity within the active site binding region of kinases makes selectivity a particular challenge that can lead to off-target effects. Our explorations of natural product and AI-generated molecular structures are revealing new kinase inhibitor scaffolds.

This seminar will focus on work involving the fungal natural product (-)-TAN-2483B, a moderately potent and selective inhibitor of Bruton’s tyrosine kinase (Btk).1 We are conducting analogue and structure-activity relationship studies, together with binding mode investigations, to evaluate the potential of the furo[3,4-b]pyran-5-one scaffold for Btk inhibition.2,3 Alongside the natural product work, we are exploring the potential of AI systems that generate novel drug-like structures to predict potent and selective kinase inhibitors.4 Through a combination of virtual screening techniques and synthetic medicinal chemistry, we are evaluating the outputs of the molecular generation systems. While in the early stages, this research is building our understanding of the strengths and limitations of molecular generators to reveal potential new kinase inhibitory therapeutics.

References

1. McCone, J. A. J.; Somarathne, K. K.; Orme, C. L.; Hewitt, R. J.; Grant, E.-R.; Hall, K. R.; Ackerley, D. F.; La Flamme, A. C.; Harvey, J. E. Org. Lett. 2020, 22, 9427–9432.
2. Somarathne, K. K.; McCone, J. A. J.; Brackovic, A.; Rivera, J. L. P.; Fulton, J. R.; Russell, E.; Field, J. J.; Orme, C. L.; Stirrat, H. L.; Riesterer, J.; Teesdale-Spittle, P. H.; Miller, J. H.; Harvey, J. E. Chem. – Asian J. 2019, 14, 1230–1237.
3. A Structure-Activity Investigation of the Fungal Metabolite (-)-TAN-2483B: Inhibition of Bruton’s tyrosine kinase. Jordan McCone, Paul H. Teesdale-Spittle, Jack U. Flanagan, Joanne E. Harvey Chem. Eur. J. 2024, 30, e202401051
4. H. Nguyen, G. Rajendran, P. Teesdale-Spittle, J. Harvey, B. Nguyen. Manuscript in preparation.

Biography

Joanne Harvey is an Associate Professor of chemistry at Te Herenga Waka | Victoria University of Wellington, Aotearoa New Zealand. She teaches and researches in organic chemistry, with specialities in organic synthesis, mechanism, transition metal catalysis, and medicinal chemistry. Joanne is currently the Past President of the New Zealand Institute of Chemistry (NZIC).

Joanne studied at Victoria University of Wellington (BSc Hons), and the Australian National University (PhD with Prof Martin Banwell). Postdoctoral work at the University of York with Professor Richard Taylor was supported by Anglo-Australian (2001-2002) and Ramsay Memorial Trust (2002–2004) Postdoctoral Fellowships. Since 2004, Joanne has been an academic back at her alma mater Victoria University of Wellington.