Krause, Guenter, Hassenrueck, Floyd and Hallek, Michael (2018). Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib. Drug Des. Dev. Ther., 12. S. 2577 - 2591. ALBANY: DOVE MEDICAL PRESS LTD. ISSN 1177-8881

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Abstract

On the occasion of its recent approval for relapsed follicular lymphoma, we review the design and development of the pan-class I PI3K inhibitor copanlisib as a drug for the treatment of B-cell malignancies in comparison with other kinase inhibitors targeting B-cell-receptor signaling, in particular with strictly isoform-delta-selective idelalisib. In agreement with previously defined PI3K-inhibitor chemotypes, the 2,3-dihydroimidazo[1,2-c] quinazoline scaffold of copanlisib adopts a flat conformation in the adenine-binding pocket of the catalytic p110 subunit and further extends into a deeper-affinity pocket in contrast to idelalisib, the quinazoline moiety of which is accommodated in a newly created selectivity pocket. Copanlisib shows higher potency than other clinically developed PI3K inhibitors against all four class I isoforms, with approximately tenfold preference for p110 alpha and p110 delta. Owing to its potency and isoform profile, copanlisib exhibits cell-type-specific cytotoxicity against primary chronic lymphocytic leukemia cells and diffuse large B-cell lymphoma (DLBCL) cell lines at nanomolar concentrations. Moreover, copanlisib differs from idelalisib in regard to intravenous versus oral administration and weekly versus twice-daily dosing. In regard to adverse effects, intermittent intravenous treatment with copanlisib leads to fewer gastrointestinal toxicities compared with continuous oral dosing of idelalisib. In relapsed follicular lymphoma, copanlisib appears more effective and especially better tolerated than other targeted therapies. Copanlisib extends existing treatment options for this subtype of indolent non-Hodgkin lymphoma and also shows promising response rates in DLBCL, especially of the activated B-cell type.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Krause, GuenterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hassenrueck, FloydUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-200308
DOI: 10.2147/DDDT.S142406
Journal or Publication Title: Drug Des. Dev. Ther.
Volume: 12
Page Range: S. 2577 - 2591
Date: 2018
Publisher: DOVE MEDICAL PRESS LTD
Place of Publication: ALBANY
ISSN: 1177-8881
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; PHOSPHATIDYLINOSITOL 3-KINASE INHIBITION; 1ST-IN-HUMAN PHASE-I; PHOSPHOINOSITIDE 3-KINASE; BAY 80-6946; CHEMOTHERAPEUTIC-AGENTS; DOSE-ESCALATION; LYMPHOMA; PI3K-DELTA; SURVIVALMultiple languages
Chemistry, Medicinal; Pharmacology & PharmacyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20030

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