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

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.

Keywords: B-cell receptor signaling; leukemia; non-Hodgkin lymphoma; p110 isoforms; targeted therapy.

Conflict of interest statement

Disclosure GK has received research funding from Bayer, Roche, and Boehringer Ingelheim. MH has received consultancy fees and honoraria from AbbVie, Mundipharma, GlaxoSmithKline, Gilead, and Celgene; consultancy, honoraria, and speakers bureau fees from Janssen; consultancy and speakers bureau fees from Pharmacyclics; consultancy, research funding, and speakers bureau fees from Roche; and funding from Gilead. The authors report no other conflicts of interest in this work.

Figures

Figure 1

Molecular structure of copanlisib. Notes: Elements of the initial lead are shown in black and subsequent modifications in blue. The structure–activity relationship of the highlighted positions of the 2,3-dihydroimidazo[1,2-c]quinazoline scaffold was explored extensively by numerous substitutions, as outlined in the “Design and structure -activity relationship” section. Red print indicates potential binding regions in the p110γ structure, as well as contact residues.

Figure 2

Inhibitor binding to p110 isoform-binding pockets. Notes: Views of the ATP-binding clefts of p110γ or p110δ cocrystallized with copanlisib (A) or idelalisib (B) were captured from the RCSB PDB entries 5G2N and 4XE0, respectively, visualized on www.rcsb.org with the NGL viewer., The binding pockets opening toward the left were aligned according to the highlighted methionine residues M804 or M752 and tryptophan residues W812 or W760 of p110γ or p110δ, respectively, that form an induced cleft accommodating the quinazoline moiety of idelalisib (B). Instead, the flat copanlisib molecule extends into the deeper affinity pocket of p110γ, making contact with the circled side chains of K833, D836, and D841 (A). Both inhibitors contact the highlighted valine residues of the hinge regions V882 (A) or V828 (B). The hinge regions connect the N-terminal (top) and C-terminal (bottom) lobes of p110 and roughly delimit the ATP-binding and affinity pockets in the views depicted. Abbreviation: RCSB PDB, Research Collaboratory for Structural Bioinformatics Protein Data Bank.

Figure 3

Isoform-selectivity profiles of PI3K inhibitors in clinical use or development. Notes: Inhibitor potency against purified p110 catalytic subunits is represented by IC50 values determined in activity assays. Isoform-selectivity profiles are shown for the isoform-selective inhibitors idelalisib, duvelisib, and alpelisib, which show at least 50-fold higher potency for a certain isoform, and the pan-class I inhibitors buparlisib, pilaralisib, pictilisib, AZD8835, and copanlisib. Figures above the columns indicate the exact individual IC50 (nM) values. Abbreviation: IC50, half maximal inhibitory concentration.

Figure 4

Involvement of PI3Kδ and lipid second messengers in B-cell-receptor signaling. Notes: Activation of PI3Kδ upon stimulation of the B-cell receptor occurs via recruitment of p85 to a phosphotyrosine-docking site created by the Src-family kinase Lyn. PI3K activity leads to production of lipid second messengers and is counteracted by the phosphatases PTEN and SHIP. Red arrows indicate the activation of the kinases Akt and BTK by binding of lipid second messengers to their pleckstrin-homology domains that enables their localization at the plasma membrane. Further signaling events lead to regulation of transcription-factor activity. Abbreviation: DAG, diacylglycerol.

Figure 5

Different adverse effects of copanlisib and idelalisib. Notes: The incidence of the adverse effects named among participants in trials assessing copanlisib or idelalisib was compared. With 141 and 125 study participants, respectively, the trials were of comparable size, and both Phase II studies comprised patients with relapsed indolent NHL. All adverse-effect categories affecting .10% of participants are listed, with those occurring exclusively with copanlisib printed in blue.