Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors

Porter, John; Payne, Andrew; Candole, Ben de; Ford, Daniel; Hutchinson, Brian; Trevitt, Graham; Turner, James M. A.; Edwards, C H; Watkins, Clare; Whitcombe, Ian; Davis, Jeremy; Stubberfield, Colin R.

doi:10.1016/j.bmcl.2008.10.113

Cited by 89 publications

(62 citation statements)

References 18 publications

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“…6,22 In agreement, ABT-263 induced a concentration-dependent cell death (assessed by phosphatidylserine (PS) externalisation) in BAK-reconstituted but not in BAK-deficient Jurkat cells (Figure 2). UCB-1350883, 23 identified by a high throughput screen as a moderately potent and selective inhibitor of BCL-2, exhibited some selectivity in inducing apoptosis only in the presence of BAK, albeit at high concentrations (30 mM). However, neither ABT-263 nor UCB-1350883 was designed to inhibit MCL-1.…”

Section: Resultsmentioning

confidence: 99%

Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Evaluation and critical assessment of putative MCL-1 inhibitors

et al. 2013

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“…39 Variation of R 1 and R 2 on this scaffold gave IC 50 values from 5 to 20 μM against the complex of Bcl-x L and Bak 16-mer peptide. In our MS screen against Bcl-x L we expected, therefore, to generate a substantial number of binding ligands with the current library.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

Automated Protein–Ligand Interaction Screening by Mass Spectrometry

et al. 2012

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Identifying protein-ligand binding interactions is a key step during early-stage drug discovery. Existing screening techniques are often associated with drawbacks such as low throughput, high sample consumption, and dynamic range limitations. The increasing use of fragment-based drug discovery (FBDD) demands that these techniques also detect very weak interactions (mM K(D) values). This paper presents the development and validation of a fully automated screen by mass spectrometry, capable of detecting fragment binding into the millimolar K(D) range. Low sample consumption, high throughput, and wide dynamic range make this a highly attractive, orthogonal approach. The method was applied to screen 157 compounds in 6 h against the anti-apoptotic protein target Bcl-x(L). Mass spectrometry results were validated using STD-NMR, HSQC-NMR, and ITC experiments. Agreement between techniques suggests that mass spectrometry offers a powerful, complementary approach for screening.

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“…For docking studies three-dimensional structures of antiapoptotic proteins such as BCL-2, BCL-XL, and MCL-1 were retrieved from the RCSB protein data bank 13,21 with their respective PDB id's 2W3L 22 , 2YXJ 23 , and 3KZ0 24 . These protein structures were determined using X-ray diffraction methods.…”

Section: Protein Preparationmentioning

confidence: 99%