Jonathan M. Large's scientific contributions

What is this page?

This page lists the scientific contributions of an author, who either does not have a ResearchGate profile, or has not yet added these contributions to their profile.

It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.

If you're a ResearchGate member, you can follow this page to keep up with this author's work.

If you are this author, and you don't want us to display this page anymore, please let us know.

Publications (1)

FIGURE 1
FIGURE 2 (A) Chemical space representation for CNS (Pfizer MPO) vs Ro5 (Lipinski et al., 2001; Veber et al., 2002) bRo5 (Doak et al., 2014; Villar et al., 2014; Poongavanam et al., 2018) and PROTAC guidelines (Hornberger and Araujo, 2023) for oral absorption. Red data point refers to unsatisfied HBDintramolecular hydrogen bond pairs not counted. MGD designs would be expected to fall within Ro5/CNS metric space. (B) PROTAC specific values vs different metrics or limitations identified from bRo5 space studies (Degoey et al., 2018). (C) Several TPSA guidelines (E) scaled by MW; (Whitty et al., 2016; Mobitz, 2023) black lines are TPSA = 0.1, 0.2, 0.3*MW, plotted points are the MW and TPSA outer limits of metric sets from (A,B). The green arrow shows the TPSA difference between Ro5 and CNS Ro5 space. The purple arrow represents the TPSA vs minimum/3D PSA difference seemingly required for bRo5 oral absorption. BBB penetration will impose stricter minimum/3D PSA limitations and a correspondingly larger ΔPSA is likely necessary (orange). (D) Numerical values plotted in (A,B) for different metric spaces. (E). Polarity based chameleonicity or ΔPSA/3D TPSA metrics defined in the literature (Whitty et al., 2016; Garcia Jimenez et al., 2023; Mobitz, 2023).
Targeted protein degradation in CNS disorders: a promising route to novel therapeutics?
  • Literature Review
  • Full-text available

April 2024

·

40 Reads

Frontiers in Molecular Neuroscience

Sandra Kuemper

·

Andrew G. Cairns

·

Kristian Birchall

·

[...]

·

Jonathan M. Large

Targeted protein degradation (TPD) is a rapidly expanding field, with various PROTACs (proteolysis-targeting chimeras) in clinical trials and molecular glues such as immunomodulatory imide drugs (IMiDs) already well established in the treatment of certain blood cancers. Many current approaches are focused on oncology targets, leaving numerous potential applications underexplored. Targeting proteins for degradation offers a novel therapeutic route for targets whose inhibition remains challenging, such as protein aggregates in neurodegenerative diseases. This mini review focuses on the prospect of utilizing TPD for neurodegenerative disease targets, particularly PROTAC and molecular glue formats and opportunities for novel CNS E3 ligases. Some key challenges of utilizing such modalities including molecular design of degrader molecules, drug delivery and blood brain barrier penetrance will be discussed.

Download
Share