Degraders early developability assessment: face-to-face with molecular properties. Issue 9 (September 2020)

• Record Type: Journal Article
• Authors: Ermondi, Giuseppe; Vallaro, Maura; Caron, Giulia
• Is Part Of: Drug discovery today. Volume 25:Issue 9(2020)
• Page Start: 1585
• Page End: 1591
• Publication Date: 2020-09
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2020.06.015
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: Degraders could revolutionize future drug discovery. Degraders are large and flexible compounds that do not comply with Lipinski's Ro5. Property-based drug design of degraders cannot be performed with common tools used for Ro5-compliant compounds. Ionization, lipophilicity, polarity and chameleonicity of degraders are experimentally accessible. For a small dataset of degraders permeability is governed by polarity expressed as Δlog kW IAM . 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 kW IAM – 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.