Highly selective and high-affinity autophagy inhibitors for development in oncology

The University of Antwerp has discovered the most potent and selective small molecule autophagyinhibitors reported to date.  Compounds target autophagy in a highly specific manner, via inhibitionof the cysteine protease Atg4B.  Target audience for the technology: pharma/biotech partners thatare looking for a development candidate in oncology.

Situation before 

In oncology, autophagy has been reported toplay distinct and functionally ambiguous roles,depending on the stage of the disease.  Inhibitionof autophagy has been shown to increase andrestore sensitivity to cytotoxic therapy and topromote tumor cell death, both in vitro and invivo.  All currently known autophagy inhibitorshave low intrinsic potency and act in a nonspecific manner, mostly interfering upstreamof autophagosome formation and affecting avariety of processes.  Atg4B is a cytosolic enzymethat processes so called Light Chain Proteins(LCPs), essential chaperones for autophagosomeformation. Interference with LCP-processing viablocking of Atg4B activity, has been shown to bean effective means for autophagy inhibition.  Todate, only low-affinity Atg4B inhibitors withoutpractical value in translational settings havebeen reported in literature.

Technology 

Lead compound UAMC-2526 is currentlythe most advanced candidate for furtherdevelopment. The compound induces completeresistance to starvation-induced autophagy inliver cells of healthy mice. More importantly, ina mouse HT29 tumor xenograft model of humancolorectal cancer, the compound significantlyincreased therapeutic response to the cytostaticstandard of care, oxaliplatin. So far, during a 28-day treatment regimen in mice, UAMC-2526did not cause any observable toxicity. Ourdata demonstrate that UAMC-2526 could bea very promising candidate for oncology drugdevelopment.  It has the potential to act as abooster for targeted oncology therapies byincreasing and restoring sensitivity to cytotoxic therapy, thereby promoting tumor cell death.  We are currently planning further studies whereUAMC-2526 is tested in 4 additional modelsof human cancer.  At the same time, we arepreparing additional analogues of UAMC-2526that could serve as eventual back-up candidates.

About the researchers 

The Medicinal Chemistry (contact: Prof. P. Vander Veken), the Physiopharmacology (contact:Prof. W. Martinet), the Molecular ImagingCenter Antwerp (contact: Prof. S. Stroobants)and the Center for Oncological Research(contact: Prof. M. Peeters) groups have adurable joint multidisciplinary collaborationon inhibitor discovery for Atg4B in the field ofoncology.  Previous collaborations betweenthese groups have already resulted in severalpublications and a joint patent application,and combine expertise from three differentpreclinical disciplines: basic drug discovery,pharmacology and in vivo biology.

More information

University of Antwerp

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