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

Drug Design, Development and Therapy
Günter KrauseMichael Hallek

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-...Continue Reading

Citations

Mar 1, 2019·Biomolecules·Michelle S MillerSandra B Gabelli
Jun 25, 2020·Expert Review of Clinical Pharmacology·Massimo MagagnoliArmando Santoro
Sep 8, 2020·Drugs·Sara E Nunnery, Ingrid A Mayer
Jun 20, 2019·Frontiers in Oncology·Stefania CrisciAntonio Pinto
Jan 24, 2019·International Journal of Molecular Sciences·Vanessa Edna SanchezYong-Mi Kim
Dec 9, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Folayemi AdefemiAaron J Marshall
Dec 14, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elizabeth A LemmGraham Packham
May 7, 2020·Molecular Cancer Therapeutics·Alfonso García-ValverdeCésar Serrano
Nov 3, 2020·Clinical Lymphoma, Myeloma & Leukemia·Tycel J PhillipsVincent Ribrag
Feb 4, 2021·Cancer Management and Research·Ayushi F Chauhan, Bruce D Cheson
Apr 4, 2021·Cancers·Valerio Guarente, Paolo Sportoletti
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Aug 7, 2021·Genes·Cristina CuestaEsther Castellano

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