Unbiased assessment of P-gp efflux towards designing blood—brain barrier penetrant compounds

The blood—brain barrier (BBB) presents a major hurdle in development of CNS-active therapeutics, and expression of P-glycoprotein (P-gp) efflux transporter at blood-brain interface further impedes BBB penetrance of most small-molecules. Designing out efflux from compounds can be laborious, and there is currently no generalizable approach to directly transform periphery-limited agents to ones active in the CNS. Here we describe a target-agnostic, prospective assessment of P-gp efflux using diverse compounds. Our results demonstrate that reducing molecular size or appending a carboxylic acid enables evasion of P-gp in cell-based experiments and in mouse models. These strategies were then applied transform a periphery-limited V600EBRAF inhibitor, dabrafenib, into versions that possess potent and selective anticancer activity but now also evade P-gp-mediated efflux. When compared to dabrafenib, the lead compound developed herein (everafenib) has superior BBB penetrance, and superior efficacy in an intracranial mouse model of metastatic melanoma, suggesting it as a lead candidate for the treatment of melanoma metastases to the brain and gliomas with BRAF mutation. More generally, the results described herein suggest the actionability of the trends observed in these target-agnostic efflux studies and provide guidance for the conversion of non-BBB penetrant drugs into versions that are BBB penetrant and efficacious.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Kelly, Aya Matsunaga

Contributors dc:contributor

• Hergenrother, Paul J
• van der Donk, Wilfred
• Mitchell, Douglas A
• Zimmerman, Steven C

• blood—brain barrier
• P-glycoprotein
• BRAF inhibitor

Statement dc:rights

• Copyright 2022 Aya Kelly

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115701

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115701