Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors

Davis, Owen A.; Cheung, Kwai-Ming J.; Brennan, Alfie; Lloyd, Matthew G.; Rodrigues, Matthew J.; Pierrat, Olivier A.; Collie, Gavin W.; Bihan, Yann‐Vaï Le; Huckvale, Rosemary; Harnden, Alice C.; Varela, Ana; Bright, Michael D.; Eve, Paul D.; Hayes, Angela; Henley, Alan T.; Carter, Michael D.; McAndrew, P.C.; Talbot, Rachel; Burke, Rosemary; Montfort, R.L.M. van; Raynaud, Florence I.; Rossanese, Olivia W.; Meniconi, Mirco; Bellenie, Benjamin R.; Hoelder, Swen

doi:10.1021/acs.jmedchem.1c02174

Cited by 16 publications

(24 citation statements)

References 28 publications

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“…This assertion is suggested by the fact that 10 nM TCIP1 produces only a modest, ~1.5-fold increase in BRD4 at BCL6 sites over the genome (Fig 5), despite robust gene activation and cell killing. This observation could also explain the far more robust cell killing seen with substantially lower concentrations of TCIP1, compared to the weaker anti-proliferative effects of conventional small molecule inhibitors or degraders of BCL6 35,[67][68][69][70][71] or BRD4 37 , which act by "occupancy-driven" pharmacology requiring binding to almost all copies of their cognate protein. As a consequence, TCIPs may avoid mechanism-based toxicity that almost inevitably occurs when one reduces the expression or activity of an essential protein, like BRD4.…”

Section: Tcip1 Appears To Be Relatively Non-toxic In Primary Human Ce...mentioning

confidence: 99%

Rewiring Cancer Drivers to Activate Apoptosis

Gourisankar¹,

Krokhotin²,

Ji³

et al. 2022

Preprint

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Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1–6. Independent studies have identified cell death pathways that eliminate cells for the good of the organism7–10. The coexistence of the cell death pathways with the driver mutations suggest that the cancer driver could be rewired to activate cell death. We have invented a new class of molecules: TCIPs (Transcriptional/Epigenetic Chemical Inducers of Proximity) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes thereby activating their expression. To develop this concept, we have focused on diffuse large B cell lymphoma (DLBCL), in which BCL6 is amplified or mutated11. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression12. We produced the first TCIPs by chemically linking BCL6 inhibitors to small molecules that bind transcriptional activators. Several of these molecules robustly kill DLBCL at single-digit nanomolar concentrations, including chemotherapy-resistant, TP53-mutant lines. The dominant gain-of-function approach provided by TCIPs captures the combinatorial specificity inherit to transcription and can thereby accesses new therapeutic space. TCIPs are relatively non-toxic to normal cells and mice, apparently reflecting their need for coincident expression of both target proteins for effective killing. The general TCIP concept has applications in elimination of senescent cells, enhancing expression of therapeutic genes, treatment of diseases produced by haploinsufficiency, and activation of immunogens for immunotherapy.

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Section: Tcip1 Appears To Be Relatively Non-toxic In Primary Human Ce...mentioning

confidence: 99%

Rewiring Cancer Drivers to Activate Apoptosis

Gourisankar¹,

Krokhotin²,

Ji³

et al. 2022

Preprint

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“…By using a combination of biochemical and biophysical assays, followed by structural confirmation using X-ray crystallography, we were able to overcome each hit validation method's respective limitations and effectively triage hit compounds, identifying several validated and structurally characterised hit series and singletons. The in vitro TR-FRET assay proved instrumental in the optimisation of biochemical potency and the InCell Hunter and NanoBRET assays were crucial in assessing the cellular activity of the compounds, thus aiding the discovery of a series of potent benzimidazolone-and quinolinone-based BCL6 inhibitors showing sub-micromolar cellular activity and antiproliferative effect in the BCL6-dependent lymphoma cell lines OCI-LY1 and SU-DH-L4 15,40 .…”

Section: Discussionmentioning

confidence: 99%

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays

Pierrat

Liu

Collie

et al. 2022

Sci Rep

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By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein–protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.

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“…Our BCL6 degraders consisted of two key elements: (1) a central benzimidazolone core that bound to BCL6 and (2) a substituted piperidine that conveys the ability to induce BCL6 degradation. To identify advanced degraders, we discovered a tricyclic core that showed hundredfold tighter binding to BCL6 than our initial benzimidazolone core [ 13 ]. In addition, we identified alternative piperidine moieties that we significantly less hydrophobic but still capable to induced degradation [ 14 ].…”

Section: Keynote Lecturesmentioning

confidence: 99%