Pharmaceutical scientists have huge expectations from heterobifunctional small molecule degraders to treat diseases with an unmet medical need. However, degraders are large and flexible and pose significant challenges in terms of cellular uptake and bioavailability. An efficient property-based design is therefore required to discover new oral degrader medicines. Here, we show the non‑transferability to degraders of in silico tools routinely implemented in small molecule drug discovery programs; and provide ionization, lipophilicity, polarity and chameleonicity data for a series of seven degraders. We also reveal that permeability can be modeled by Δlog kWIAM – an experimental polarity descriptor. Overall, the paper is a proof-of-concept that shows to discover new oral degrader drugs ad hoc property-based design strategies are required.

Degraders early developability assessment: face-to-face with molecular properties

Ermondi G.
First
;
Vallaro M.;Caron G.
Last
2020-01-01

Abstract

Pharmaceutical scientists have huge expectations from heterobifunctional small molecule degraders to treat diseases with an unmet medical need. However, degraders are large and flexible and pose significant challenges in terms of cellular uptake and bioavailability. An efficient property-based design is therefore required to discover new oral degrader medicines. Here, we show the non‑transferability to degraders of in silico tools routinely implemented in small molecule drug discovery programs; and provide ionization, lipophilicity, polarity and chameleonicity data for a series of seven degraders. We also reveal that permeability can be modeled by Δlog kWIAM – an experimental polarity descriptor. Overall, the paper is a proof-of-concept that shows to discover new oral degrader drugs ad hoc property-based design strategies are required.
2020
25
9
1585
1591
Degraders, bR05, Permeability, Bioavailability, Drug Discovery
Ermondi G.; Vallaro M.; Caron G.
File in questo prodotto:
File Dimensione Formato  
Ermondi2020Degraders.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 1.38 MB
Formato Adobe PDF
1.38 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1765634
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 31
  • ???jsp.display-item.citation.isi??? 30
social impact