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. 2014 Mar 21;5(6):662-7.
doi: 10.1021/ml500030p. eCollection 2014 Jun 12.

Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

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Free PMC article

Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

Michael F T Koehler et al. ACS Med Chem Lett. .
Free PMC article

Abstract

Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.

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

Figures

Figure 1
Figure 1
BCL-XL antagonists 1 and 2 incorporating a hydrazone linker between the benzothiazole and bicyclic core. Rat PK data represents an average of three animals dosed at 1 mg/kg IV or 5 mg/kg PO.
Figure 2
Figure 2
Interactions of compound 1 with BCL-XL observed in a 2.3 Å resolution crystal structure (PDB: 3ZLN). The surface displayed is one van der Waal’s radius above the analytic Connolly surface of the protein. Hydrogen bonds are indicated by dashed lines.
Figure 3
Figure 3
Initially prepared analogues of 1 along with their inhibitory activity toward BCL-XL. Compounds 5 and 6 were assayed as single enantiomers. Their absolute configuration was not determined.
Figure 4
Figure 4
Tetrahydroisoquinolines with and without extensions into the P4 pocket along with AlphaScreen measured IC50 values for BCL-XL. Compounds 19 and 20 were synthesized as the trans isomer.
Scheme 1
Scheme 1. Synthesis of Tetrahydroisoquinolines 13 and 14
Reagents and conditions: (a) benzo [d]thiazol-2-amine, EDCI, DMAP, DCM; (b) 2 N HCl/Et2O, DCM; (c) t-butyl 6-fluoropyridine-2-carboxylate, Cs2CO3, DMA, sieves, 100 °C, 29%; (d) HCl, EtOH, H2O, 67%; (e) methyl 2-chlorothiazole-4-carboxylate, Cs2CO3, DMA, 50 °C, 67%; (f) 2 N NaOH, THF/MeOH, 50 °C.
Figure 5
Figure 5
Interactions of compound 20 with BCL-XL observed in a 2.35 Å resolution crystal structure. The surface displayed is one van der Waal’s radius above the analytic Connolly surface of the protein. Hydrogen bonds are indicated by dashed lines.

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