Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy

Abstract

Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.

Keywords: Bcr-Abl; Bosutinib; Dasatinib; Imatinib; Leukemia; Nilotinib; Ponatinib; Structure-activity relationship; Targeted therapy; Tyrosine kinase inhibitors (TKIs).

Fig. 1

Structural 3D model of Bcr-Abl catalytic domain. The ribbon diagram of crystal structure shows the N-lobe at the top (dark gray) and C-lobe at the bottom (green), rich in β-sheets and α-helices respectively. The catalytic segment (yellow), the P-loop (red), the activation loop (orange), and the hinge region (light blue) stand in the middle. Key amino acidic residues are indicated in magenta circles: Thr315 (T315) is the gatekeeper residue within the ATP-binding pocket (black arrow), Asp363 (D363) is pivotal for nucleophilic attack on peptide substrate during catalysis, Tyr393 (Y393) is the target of phosphorylation that controls Abl activation and inactivation, whereas the DFG (Asp-Phe-Gly) motif coordinates fundamental cofactors for catalysis, namely Mg²⁺ ions [88]

Fig. 2

Asp363 protonation during catalysis. Here, the reaction mechanism of substrate phosphorylation is shown. The nucleophilic attack of D363 on hydroxyl group of peptide substrate leads to its transient protonation that in turn causes conformational changes to inactive state. (R = peptide substrate, D = aspartate, K = lysine, E = glutamate, S = serine)

Fig. 3

Chemical optimization and functions of imatinib structure. The phenylaminopyrimidine derivative lead compound is indicated in black. ① The pyridyl group (red) added at 3′-position of the pyrimidine moiety enhanced cellular activity, ② the amide substituent (blue) on the phenyl ring provided the molecule with inhibitory activity against tyrosine kinases, and ③ the 6-methyl (green) addition to the central aminophenyl ring nullified the unspecific activity on PKC, thus increasing selectivity of the compound for Bcr-Abl. Finally, ④ an N-methylpiperazine (purple) was added to enhance aqueous solubility and oral bioavailability of the drug, but ⑤ required the insertion of the amide linker and a benzene ring (yellow) as a spacer to abolish the mutagenic potential of the aniline moiety otherwise obtained. Imatinib was therefore developed as optimized Bcr-Abl oral inhibitor

Fig. 4

a–d Structure comparison of Bcr-Abl clinically approved inhibitors. Chemical structures are here represented in color code with regard to analogous groups of different tyrosine kinase inhibitors (green: core structure; red and blue: substituents group)

Fig. 5

a–g Structure comparison of Bcr-Abl preclinically validated inhibitors. Chemical structures are here represented in color code with regard to analogous groups of different tyrosine kinase inhibitors (green: core structure; red and blue: substituents group)