2026-09-22T06:09:08Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/115701 2023-07-11 col_2142_5131 col_2142_14789 com_2142_5130 com_2142_14788 com_2142_8903

The student, Aya Kelly, accepted the attached license on 2022-04-15 at 10:24. The student, Aya Kelly, submitted this Dissertation for approval on 2022-04-15 at 10:33. This Dissertation was approved for publication on 2022-04-19 at 17:15. DSpace SAF Submission Ingestion Package generated from Vireo submission #17698 on 2022-11-11 at 12:47:01 Hergenrother, Paul J Hergenrother, Paul J van der Donk, Wilfred Mitchell, Douglas A Zimmerman, Steven C 2022-05 application/pdf en text Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01 Unbiased assessment of P-gp efflux towards designing blood—brain barrier penetrant compounds Kelly, Aya Matsunaga 2022-04-19 blood—brain barrier P-glycoprotein BRAF inhibitor 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. Thesis eng https://hdl.handle.net/2142/115701 Copyright 2022 Aya Kelly Ph.D. Dissertation Chemistry University of Illinois at Urbana-Champaign Chemistry