Industry Talk - AstraZeneca

2027-01-13 14:00:00 – 2027-01-13 15:30:00
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Conformational Design of PROTACs for the clinic


Markus Schade, James S. Scott, Laura Evans, Sharan K. Bagal, Claire Crafter, Coura Diène, Michael J. Niedbala, Antonio Ramos-Montoya, Martin J. Packer, Andy Pike


1Chemistry and DMPK, Oncology Targeted Discovery, AstraZeneca, 1 Francis Crick Avenue, Cambridge CB2 0AA, United Kingdom


Designing favourable conformational properties and oral bioavailability into Proteolysis Targeting Chimeras (PROTACs) is a key challenge [1]. Here we show the conformational differences between cellular tool and oral clinical-stage PROTACs. We introduce a new, broadly applicable 1H-NMR method that categorises H-bond donors (HBD) into solvent-exposed, solvent-shielded and chameleonic HBDs and demonstrate that oral, clinical-stage PROTACs contain no more than 2 solvent-exposed HBDs, but up to 5 formal HBDs (Fig. 1) [2]. We summarize our findings in a new Rule-of-oral-PROTACs and apply these learnings to the discovery of Astrazeneca’s oral androgen receptor degrading PROTAC AZD9750 which advanced to clinical PH1 studies (NCT07336446) [3].


Markus abstract fig


Fig. 1. Conformational and physicochemical design of AZD9750. (a) Variable temperature 1H-NMR experiments in polar DMSO-d6 and non-polar CDCl3 discriminate between chameleonic, solvent-shielded and solvent-exposed HBDs (orange). (b) Clinical oral PROTAC AZD9750 and (c) its physico-chemical properties mapped to the new Rule-of-oral-PROTACs and Rule-of-5 property spaces. (d) Extended conformation of AZD9750 as determined by NMR and its residual rotational flexibility (arrows).


References:



  1. A. Pike et al. “Lessons learned in linking PROTACs from discovery to the clinic”, Nat. Rev. Chem. (2025) DOI: 10.1038/s41570-025-00784-6

  2. M. Schade et al. “Structural and Physicochemical Features of Oral PROTACs”, J. Med. Chem., 2024, 67, 13106-13116.

  3. J. S. Scott et al. “Discovery of AZD9750, an Orally Bioavailable Androgen Receptor Degrader for the Treatment of Prostate Cancer”, J. Med. Chem. (2026) DOI: 10.1021/acs.jmedchem.5c03138