Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I^1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation

Abstract

Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of “bridge” inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation, enabling persistent sensitivity to different genetic mutations in ALK. These data highlight a rationale for further development of next-generation ALK inhibitors to combat drug resistance.

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

“…In fact, our data support that ceritinib can inhibit the efflux of ABCB1-mediated the conventional chemotherapeutic drugs to enhance the accumulation of these drugs in MDR leukemia cells, and to restore the sensitivity of ABCB1-overexpressing MDR cells to these conventional chemotherapeutic drugs, while having weak effect on their parental cells. Additionally, although ceritinib has been shown excellent antiproliferation activity in different ALK-positive cancer cells by inhibiting ALK phosphorylation and subsequent downstream survival signaling of ALK, such as ERK, p-ERK, AKT and p-AKT [41], some studies also have shown that activation of ERK or PI3K/AKT pathway is attributable to the resistance to conventional chemotherapeutic drugs in various cancer cells [42, 43]. In our study, we found that ceritinib could reverse ABCB1-mediated MDR and enhance the efficacy of conventional chemotherapeutic drugs at more than 85% cell survival concentration.…”

Size‐Transformable Metal–Organic Framework–Derived Nanocarbons for Localized Chemo‐Photothermal Bacterial Ablation and Wound Disinfection

“…To address the infection of pathogenic bacteria, antibiotics are inevitably and excessively utilized in clinical disinfection therapies. However, up to now, the adaptive tendency of pathogens on drug resistance produces a great threat to current therapeutic systems in combating diverse bacterial infections . Hence, novel and efficient antibacterial materials and strategies are urgently needed to reduce the dependence on antibiotic treatments .…”

Insight into the selective mechanism of phosphoinositide 3‐kinase γ with benzothiazole and thiazolopiperidine γ‐specific inhibitors by in silico approaches

“…The binding free energy (∆ G bind ) for each system was calculated by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) methodology in AMBER according to the Equation :(Chen et al., , ; Genheden & Ryde, ; Gohlke, Kiel, & Case, ; Hou, Li, & Wang, ; Hou, Wang, Li, & Wang, ,; Hou, Zhu, Chen, & Xu, ; Liu, Yao, Wang, & Han, ; Pan et al., ; Sun, Li, Li, & Hou, ; Sun et al., ; Sun, Li, Shen, et al., ; Sun, Li, Tian, et al., ; Xu, Li, Li, Zhou, & Hou, ; Xu, Sun, Li, Wang, & Hou, ; Xue et al., ; Xue, Qi, et al., ; Xue, Wang, et al., ; Yang, Shen, Liu, & Yao, ; Yang et al., ; Zhang, Hou, Wang, & Liu, ) where ∆ E MM is the gas‐phase interaction energy between protein and ligand, consisting of electrostatic (∆ E ele ) and VDW interactions (∆ E vdw ). The polar and non‐polar contributions of the solvation free energy represented by ∆ G GB and ∆ G SA .…”