A. Sánchez-Arfelis1, A. Bertran-Mostazo2, S. Scaffidi2, R. Castaño2,
E. Molins3, X. Barril2,4, C. Escolano1, C. Galdeano2
1Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and
Institute of Biomedicine (IBUB), University of Barcelona (UB), Spain.
2Department of Pharmacy, and Pharmaceutical Technology, and Physical Chemistry, Faculty of Pharmacy
and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona (UB), Spain.
3Institute of Materials Science of Barcelona (ICMAB-CSIC), Campus UAB, E-08193 Cerdanyola, Spain.
4Catalan Institution for Research and Advanced Studies (ICREA), Spain.
asanchezarf@ub.edu
c-Myc is a key therapeutic oncogene that orchestrates a potent pro-cancer programme across
multiple cellular pathways. Previous attempts to developing any clinically useful drug directly
targeting it have been unsuccessful, partly because it is an Intrinsically Disordered Protein (IDP)
[1]. Indeed, the disordered nature of unbound c-Myc has become an inherent challenge for
standard structure-based drug development and novel drug modalities are needed to develop
therapeutics directly affecting c-Myc activity [2].
The overarching goal of our project is to develop PROTAC molecules that can bind allosterically
to the Fbxw7 E3 ligase and to c-Myc, to retarget c-Myc for degradation [3]. The Fbxw7 gene is
one of the most deregulated proteins in human cancer and the E3 ligase that naturally degrade
c-Myc [4]. Given that and the intrinsic difficulty to develop potent compounds for c-Myc, we have
hypothesised that PROTAC molecules targeting the natural pair E3 ligase-natural substrate (c-
Myc-Fbxw7) could increase the efficacy and the specificity of the degradation for several reasons:
employment of the same ubiquitination machinery, cellular and tissue co-localization, absolute
abundance.
Thus, in this communication, as a proof of concept that c-Myc is degradable with small-molecule
PROTAC, we will present the designed and synthesised first series of VHL- and CRBN-based
PROTACs using a low affinity fragment-size derivative of 10058-F4, a c-Myc small-molecule
inhibitor as the warhead ligand [5]. In fact, dose-response and proteasome-dependent
degradation assays of c-Myc are ongoing and preliminary results are going to be presented. In
parallel, following a fragment-based screening from a custom in-lab designed library of 700
fragments screened by SPR, we have identified fragments that bind to the Fbxw7 in the low
micromolar range. These fragments have been confirmed by STD-NMR and have been further
biophysically characterized. We are currently working on the binding mode and functional
implications of these fragments.
References:
[1] Yu, C.; Niu, X.,Jin, F., Liu, Z., Jin, C. et al. Sci. Rep. 2016, 6, 22298.
[2] Madden, S.K., de Araujo, A.D., Gerhardt, M. et al. Mol Cancer 2021, 20, 3.
[3] Békés, M., Langley, D.R., Crews, C.M. Nat Rev Drug Discov 2022, 21, 181–200.
[4] Welcker, M.; Clurman, B. E. Nat. Rev. Cancer, 2008, 8 (2), 83–93.
[5] Yin, X.; Giap, C., Lazo, J.S., Prochownik, E.V. Oncogene, 2003, 22, 6151-6159.
