What question did this study set out to answer?

Design and evaluate novel, orally bioavailable BTK-targeting PROTACs with modified CRBN-binding warheads to overcome drug resistance and eliminate off-target degradation.

August 16, 2026Journal of Medicinal Chemistry

Discovery ofHighly Potent and Selective, Orally BioavailableBTK-Targeting PROTACs Featuring Novel CRBN-Binding Warheads

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Authors

AMAlexey B. Mantsyzov PZPei Zhao CKChris G. Kruse

Discussion

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Overview

Preclinical study demonstrates potent BTK degradation by novel oral PROTACs in malignant B cells and mice, indicating a potential targeted therapy for resistant blood cancers.

Key Points

Design and evaluate novel, orally bioavailable BTK-targeting PROTACs with modified CRBN-binding warheads to overcome drug resistance and eliminate off-target degradation.
Designed novel CRBN-binding warheads and optimized linkers to create PROTACs targeting wild-type and mutant BTK while avoiding IKZF1, IKZF3, and GSPT1 degradation.
Evaluated BTK degradation potency (DC50) and DMPK profiles in malignant B cells and circulating B cells in mice following a single 3 mg/kg oral dose.
Lead compounds ISM-PR25 and ISM-PR44 potently degraded BTK in malignant B cells with DC50 values of 0.04 nM and 0.05 nM, respectively.
The compounds exhibited favorable DMPK profiles, avoided off-target degradation of IKZF1, IKZF3, and GSPT1, and achieved effective BTK degradation in mouse circulating B cells after a single 3 mg/kg oral dose.

Cite This Study

Mantsyzov et al. (2026) studied this question.

synapsesocial.com/papers/6a8179cbf2fb91fc834ad229 https://doi.org/10.1021/acs.jmedchem.6c01136

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August 16, 2026Journal of Medicinal Chemistry

Discovery ofHighly Potent and Selective, Orally BioavailableBTK-Targeting PROTACs Featuring Novel CRBN-Binding Warheads

View Full Paper

Ask AI

Bookmark

Authors

AMAlexey B. Mantsyzov PZPei Zhao CKChris G. Kruse

Discussion

Member takes

Overview

Preclinical study demonstrates potent BTK degradation by novel oral PROTACs in malignant B cells and mice, indicating a potential targeted therapy for resistant blood cancers.

Key Points

Design and evaluate novel, orally bioavailable BTK-targeting PROTACs with modified CRBN-binding warheads to overcome drug resistance and eliminate off-target degradation.
Designed novel CRBN-binding warheads and optimized linkers to create PROTACs targeting wild-type and mutant BTK while avoiding IKZF1, IKZF3, and GSPT1 degradation.
Evaluated BTK degradation potency (DC50) and DMPK profiles in malignant B cells and circulating B cells in mice following a single 3 mg/kg oral dose.
Lead compounds ISM-PR25 and ISM-PR44 potently degraded BTK in malignant B cells with DC50 values of 0.04 nM and 0.05 nM, respectively.
The compounds exhibited favorable DMPK profiles, avoided off-target degradation of IKZF1, IKZF3, and GSPT1, and achieved effective BTK degradation in mouse circulating B cells after a single 3 mg/kg oral dose.

Cite This Study

Mantsyzov et al. (2026) studied this question.

synapsesocial.com/papers/6a8179cbf2fb91fc834ad229 https://doi.org/10.1021/acs.jmedchem.6c01136

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