Our laboratory applies medicinal chemistry and chemical biology approaches to basic and translational research. We collaborate closely with researchers, both at the institute and externally, to undertake multidisciplinary research programs encompassing chemistry, structural biology, high throughput screening, biochemistry and biology.

A core research goal of our laboratory is to use small molecule probes to understand the key pathways—apoptosis and necroptosis—that govern whether a cell lives or dies. Cell survival or death is an important contributor to many diseases. Our research aims to novel therapies for cancers, inflammatory conditions, ischaemic brain injury and stroke.


Selected publications from Prof Guillaume Lessene

Calleja D.J., Kuchel N.W., Lu B.G.C., Birkinshaw, R.W., Klemm T., Doerflinger M., Cooney J.P., Mackiewicz L., Au A.E., Yap Y.Q., Blackmore T.R., Katneni K., Crighton E., Newman J., Call M.J., Lechtenberg B.C., Czabotar P.E., Pellegrini M., Charman S.A., Lowes K.N., Mitchell J.P., Nachbur U., Lessene G. and David Komander D. (joint senior and corresponding authors). Insights into drug repurposing, as well as specificity and compound properties of piperidine-based SARS-CoV-2 PLpro inhibitors, Frontiers Chemistry, 2022, 10, 861209. PMID: 35494659

Gardner C.R., Davies K.A, Zhang Y., Brzozowski M., Czabotar P.E., Murphy J.M., Lessene G. From (Tool)bench to bedside: the potential of necroptosis inhibitors, Journal of Medicinal Chemistry, 2023, 66, 2361. PMID: 36781172

Roy M.J., Vom A., Okamoto T., Smith B.J., Birkinshaw R.W., Yang H., Abdo H., White C.A., Segal D., Huang D.C.S., Baell J.B., Colman P.M., Czabotar P.E., Lessene G.L., Structure-Guided development of potent benzoylurea inhibitors of BCL-XL and BCL-2, Journal of Medicinal Chemistry, 2021, 64, 5447-5669. PMID: 33904752

Grohmann C., Walker F., Devlin M., Luo M.-X., Chüeh A.C., Doherty J., Vaillant F., Ho G.-Y., Wakefield M.J., Weeden C.E., Kamili A., Murray J., Po’uha S.T., Weinstock J., Kane S.R., Faux M.C., Broekhuizen E., Zheng Y., Shield-Artin K., Kershaw N.J., Tan C.W., Witchard H.M., Ebert G., Charman S.A., Street I.P., Kavallaris M., Haber M., Fletcher J.I., Asselin-Labat M.-L., Scott C.L., Visvader J.E., Lindeman G.J., Watson K.G., Burgess A.W., Lessene G., Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors, Cell Death & Disease, 2021, 12, 268. PMID: 33712556

Pierotti C., Tanzer M., Jacobsen A.V., Hildebrand J.M, Garnier J.-M., Sharma P., Lucet I.S., Cowan A., Kersten W.J.A., Luo M.-X., Liang L.-Y., Fitzgibbon C., Garnish S.E., Hempel A., Nachbur U., Huang D.C.S., Czabotar P.E., Silke J., van Delft M., Murphy J.M., Lessene G. Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway, ACS Chemical Biology, 2020, 15, 2702. PMID: 32902249

Klemm T., Ebert G., Calleja D.J., Allison C.C., Richardson L.W., Bernardini J.P., Lu B.G.C., Kuchel N.W., Grohmann C., Shibata Y., Gan Z.Y., Cooney J.P., Doerflinger M., Au A.E., Blackmore T.R., van der Heden van Noort G., Geurink P.P., Ovaa H., Newman J., Riboldi-Tunnicliffe A., Czabotar P.E., Mitchell J.P., Feltham R., Lechtenberg B.C., Lowes K.N., Dewson G., Pellegrini M.*, Lessene G.*, and David Komander D.* (*joint senior and corresponding authors) Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2, EMBO Journal, 2020, 39, e106275. Impact Factor = 9.96, Citations = 191. PMID: 32845033

van Delft M.F., Chappaz S., Khakham Y., Bui C.T., Debrincat M.A., Lowes K.N., Brouwer J.M., Grohmann C., Sharp P.P., Dagley L.F., Li L., McArthur K., Luo M.-X., Chin H.-S., Fairlie W.D., Lee E.F., Segal D., Duflocq S., Lessene R., Bernard S., Peilleron L., Nguyen T., Miles C., Wan S.S., Lane R.M., Wardak A., Lackovic K., Colman P.M., Sandow J.J., Webb A.I., Czabotar P.E., Dewson G., Watson K.G., Huang D.C.S., Lessene, G., Kile, B.T. A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis. Nature Chemical Biology, 2019, 15, 1057-1066. PMID: 31591564

McArthur K., Whitehead L.W., Heddleston J.M., Li L., Padman B.S., Oorschot V., Georghegan N.D., Chappaz S., Davidson S., Chin H.S., Lane R.M., Dramicanin M., Saunders T.L., Sugiana C., Lessene R., Osellame L.D., Chew T.-L., Dewson G., Lazarou M., Ramm G., Lessene G., Ryan M.T., Rogers K.L., van Delft M.F., Kile B.T. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science, 2018, 359, eaao6047. PMID: 29472455

Lamb R.A., Aberle N.S., Lucas N.T., Lessene G.*, Hawkins B.C.* (*co-corresponding authors). Total synthesis of (-)-spiroleucettadine. Angewandte Chemie, International Edition in English, 2017, 56, 14663-14666. PMID: 28960638

Kotschy A., Szlavik Z., Murray J., Davidson J., Maragno A.L., Le Toumelin-Braizat G., Chamrion M., Kelly G.L., Gong J.-N., Moujalled D.M., Bruno A., Csekei M., Paczal A., Szabo Z.B., Sipos S., Radics G., Proszenyak A., Balint B., Ondi L., Blasko G., Robertson A., Surgenor A., Dokurno P., Chen I., Matassova N., Smith J., Pedder C., Graham C., Studeny A., Lysiak Auvity G., Girard A.-M., Grave F., Segal D., Riffkin C.D., Pomilio G., Galbraith L.C., Aubrey B.J., Brennan M.S., Herold M.J., Chang C., Guasconi G., Cauquil N., Melciore F., Guigal-Stephan N., Lockhart B., Colland F., Hickman J.A., Roberts A.W., Huang D.C.S., Wei A.H., Strasser A., Lessene G., Geneste O. MCL1 inhibitor S63845 is tolerable and efficacious in diverse cancer models, Nature, 2016, 538, :477-482. PMID: 27760111

Koehler M.F.T., Bergeron P., Choo E., Lau K., Ndubaku C., Dudley D., Gibbons P., Sleebs B.S., Rye C., Nikolakopoulos G., Bui C., Kulasegaram S., Kersten W., Smith B.J., Czabotar P.E., Colman P.C., Huang D.C.S., Baell J.B., Watson K.G., Hasvold L., Tao Z.-F., Wang L., Souers A.J., Elmore S., Flygare J.A., Fairbrother W.J., Lessene G., Structure-guided rescaffolding of selective antagonists of BCL-XL, ACS Medicinal Chemistry Letters, 2014, 5(6), 662-667. PMID: 24944740

Lessene G.*, Czabotar P.E., Sleebs B.E., Zobel K., Lowes K.L., Adams J.M., Baell J.B., Colman P.M., Deshayes K., Fairbrother W.J., Flygare J.A., Gibbons P., Kersten W.J.A., Kulasegaram S., Moss R.M., Parisot J.P., Smith B.J., Street I.P., Yang H., Huang D.C.S., Watson K.G. Discovery, structure-guided design of a selective BCL-XL inhibitor, Nature Chemical Biology, 2013, 9(6), 390-397. PMID: 23603658

Czabotar P.E., Lessene G., Adams J.M., Strasser A. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy, invited review, Nature Reviews Molecular Cell Biology, 2013, 15(1), 49-63. (equal first author contribution). PMID: 24355989

Lessene G., Czabotar P.E., Colman P.M. Bcl-2 family antagonists for cancer therapy, Nature Reviews, Drug Discovery, 2008, 7(12), 989-1000. PMID: 19043450

Lab research projects

Interested in supporting our research?

Your support will help WEHI’s researchers make discoveries and find treatments to ensure healthier, longer lives for you and your loved ones.

Contact our friendly team to find out how you can help.