Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(37), P. 16930 - 16952

Published: Aug. 25, 2022

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 inhibitors, which, however, limitations as inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report development LRRK2 proteolysis targeting chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based ligands E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), cellular inhibitor apoptosis (cIAP) identified best degraders containing thioether-conjugated VHL ligand VH101. A second round medicinal chemistry exploration led qualifying XL01126 a fast potent multiple cell lines, DC50 values within 15–72 nM, Dmax ranging from 82 90%, degradation half-lives spanning 0.6 2.4 h. exhibits high permeability forms positively cooperative ternary complex (α = 5.7), compensates substantial loss binary binding affinities LRRK2, underscoring its strong performance cells. Remarkably, orally bioavailable (F 15%) penetrate blood–brain barrier after either oral or parenteral dosing mice. Taken together, these experiments qualify suitable probe study noncatalytic scaffolding functions vitro vivo offer attractive starting point future drug development.

Language: Английский

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Targeted protein degradation: from mechanisms to clinic

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757

Published: April 29, 2024

Language: Английский

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Proximity-Based Modalities for Biology and Medicine

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(7), P. 1269 - 1284

Published: July 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Language: Английский

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Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(12), P. 8281 - 8287

Published: June 6, 2023

Heterobifunctional PROTAC degraders are gaining attention as a differentiated therapeutic modality with the potential for oral dosing in clinic. Belonging to beyond Rule of Five domain physicochemical property space, we have sought understand determinants absorption this class molecules rapid development novel agents. We collected large data set from that been dosed orally and intravenously rats estimate fraction absorbed dosing. Through estimation, effects differential hepatic clearance normalized, allowing better assessment absorption. demonstrate less permissive than mice. The properties then evaluated once compounds rank-ordered by absorbed. derive suggested design constraints on associated higher probability being

Language: Английский

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Delivering on the promise of protein degraders

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(5), P. 410 - 427

Published: Feb. 21, 2023

Language: Английский

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Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(14), P. 9297 - 9312

Published: July 5, 2023

Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes action a large potential not only as drugs but also chemical probes. Criteria previously been established to describe potency, selectivity, properties probes that are qualified enable interrogation validation drug targets. These definitions tailored reversibly acting modulators fall short in their applicability other modalities. While initial guidelines proposed, we delineate here full set criteria for characterization covalent, irreversible well heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) molecular glue degraders. We propose modified potency selectivity compared those reversible inhibitors. discuss relevance highlight examples suitable probe pathfinder compounds.

Language: Английский

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Rules were made to be broken

Nature Reviews Chemistry, Journal Year: 2023, Volume and Issue: 7(1), P. 3 - 4

Published: Jan. 1, 2023

Language: Английский

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Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(8), P. 1516 - 1534.e9

Published: Aug. 1, 2023

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility gene regulatory signatures of sensitive resistant cell patient-derived models uncover a role for mammalian SWI/SNF remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, identify both shared cancer line-specific targets underlying state. Importantly, genetic pharmacologic disruption SMARCA4/SMARCA2 ATPases re-sensitizes subset via inhibition mSWI/SNF-mediated regulation cellular programs governing proliferation, epithelial-to-mesenchymal transition, epithelial differentiation, NRF2 signaling. These data highlight supporting suggest potential utility TKI-resistant cancers.

Language: Английский

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Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2347 - 2360

Published: Feb. 8, 2023

For oral drugs, medicinal chemists aim to design compounds with high bioavailability, of which permeability is a key determinant. Taking advantage >2000 tested in rat bioavailability studies and >20,000 Caco2 assays at Bayer, we have examined the molecular properties governing permeability. In addition classical parameters such as logD weight, also investigated relationship between calculated pKa We find that neutral retain up weight limit 700, while stronger acids bases are restricted weights 400–500. investigate trends for common hydrogen bond donors acceptors, polar surface area, aromatic ring count, rotatable bonds, including exceed Lipinski’s rule five (Ro5). These property–structure relationships combined provide guidelines bioavailable drugs both traditional “beyond 5” (bRo5) chemical space.

Language: Английский

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Advancing Strategies for Proteolysis-Targeting Chimera Design

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2308 - 2329

Published: Feb. 14, 2023

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter antitumor drug development, marked significant advances over recent years. Herein, we describe developments PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss opportunities challenges for research.

Language: Английский

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