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Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib

Authors Krause G, Hassenrück F, Hallek M

Received 27 March 2018

Accepted for publication 21 May 2018

Published 21 August 2018 Volume 2018:12 Pages 2577—2590


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Jianbo Sun

Video abstract presented by Günter Krause.

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Günter Krause, Floyd Hassenrück, Michael Hallek

Department I of Internal Medicine, University of Cologne, Center of Integrated Oncology Köln Bonn, Cologne Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

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-δ-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 p110α and p110δ. 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.

targeted therapy, B-cell receptor signaling, p110 isoforms, non-Hodgkin lymphoma, leukemia

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