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. 2014 Aug 26;5(10):1088-93.
doi: 10.1021/ml5001867. eCollection 2014 Oct 9.

Discovery of a Potent and Selective BCL-XL Inhibitor With in Vivo Activity

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Free PMC article

Discovery of a Potent and Selective BCL-XL Inhibitor With in Vivo Activity

Zhi-Fu Tao et al. ACS Med Chem Lett. .
Free PMC article

Abstract

A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

Keywords: BCL-2; BCL-XL; apoptosis; cancer.

Figures

Figure 1
Figure 1
First generation hydrazone-based BCL-XL inhibitors and second generation amide-based analogues.
Figure 2
Figure 2
Left: Highly soluble fragment 6 identified as a 2nd site binder by NMR in the presence of core 1. Right: NMR-derived ternary structure of 1 (green) and 6 (magenta) bound to BCL-XL.
Figure 3
Figure 3
X-ray crystal structure of compound 10 (green) bound to BCL-XL. Protein is shown as a ribbon diagram where key amino acids are colored orange, oxygen atoms are red, and nitrogen atoms are blue. Key hydrogen bonds are shown in red dotted lines. PDB code: 4TUH.
Figure 4
Figure 4
X-ray crystal structure of A-1155463 (green) bound to BCL-XL. Key amino acids are colored orange, oxygen atoms are red, and nitrogen atoms are blue. Dotted contacts are <4 Å. PDB code: 4QVX.
Figure 5
Figure 5
(a) Kinetics of platelet reduction and rebound following a single IP dose of A-1155463 in SCID-Beige mice. Nontumor bearing female SCID-Beige mice were treated with a single dose of A-1155463 (5 mg/kg, IP). Blood samples were collected by means of retro-orbital bleeds at regular time intervals. The number of platelets was plotted as a function of time. Each point reflects the average of 5 biological replicates. Each box indicates the median ± SEM. The error bars reflect minimum and maximum values (n = 5 per time point). The colored boxes represent upper and lower quartiles. The horizontal lines within each colored box represent the mean, and the whiskers are the upper and lower range. (b) Inhibition of H146 SCLC xenograft growth by A-1155463. Female SCID-Beige mice bearing NCI-H146 subcutaneous xenografts were treated with A-1155463 (5 mg/kg IP, QDx14) or an equal volume of the vehicle (5% DMSO, 10% EtOH, 20% Cremophor ELP, and 65% D5W; n = 5 per time point) and changes in tumor volume determined as a function of time. Each point reflects the average volume of 5 tumors. Points with significant (Student’s t test, p < 0.05) difference between treated and untreated groups are indicated by means of asterisks. Tumor volume was calculated by W2·L·0.5 where W and L are two perpendicular diameters indicating width and length, respectively.

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