A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb

Joy, Stephen T.; Henley, Matthew J.; Salle, Samantha N. De; Beyersdorf, Matthew S.; Vock, Isaac W; Huldin, A. J. L.; Mapp, Anna K.

doi:10.1021/jacs.1c04432

Cited by 25 publications

(33 citation statements)

References 54 publications

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“…No binding was observed for the M/M-5A peptide. These values are in good agreement with a recent report for a similar peptide fusion of MYB and MLL, which reported K d values in the low nanomolar range for the CREBBP/ EP300 KIX domain (31).…”

Section: An Alanine-versus-aspartate Difference In the Ep300 And Creb...supporting

confidence: 93%

KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer

et al. 2022

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EP300, a transcription coactivator important in proliferation and differentiation, is frequently mutated in diverse cancer types, including small cell lung cancer (SCLC). While these mutations are thought to result in loss of EP300 function, the impact on tumorigenesis remains largely unknown. Here, we demonstrate that EP300 mutants lacking acetyltransferase domain accelerate tumor development in mouse models of SCLC. However, unexpectedly, complete Ep300 knockout suppresses SCLC development and proliferation. Dissection of EP300 domains identified kinase inducible domain-interacting (KIX) domain, specifically its interaction with transcription factors including MYB, as the determinant of protumorigenic activity. Ala 627 in EP300 KIX results in a higher protein-binding affinity than Asp 647 at the equivalent position in CREBBP KIX, underlying the selectivity of KIX-binding partners for EP300. Blockade of KIX-mediated interactions inhibits SCLC development in mice and cell growth. This study unravels domain-specific roles for EP300 in SCLC and unique vulnerability of the EP300 KIX domain for therapeutic intervention.

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Section: An Alanine-versus-aspartate Difference In the Ep300 And Creb...supporting

confidence: 93%

KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer

et al. 2022

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“…The conformational plasticity of KIX and a lack of contiguous binding pockets on its surface have made the discovery of potent ligands difficultmany small molecules and peptides designed or isolated from the above strategies have shown weak affinity in the high micromolar to millimolar range for KIX. A potent peptide ligand that links cMyb and MLL sequences was recently described; this study further illustrates the challenge in targeting an individual KIX cavity with low to medium molecular weight compounds …”

Section: Introductionmentioning

confidence: 64%

“…A potent peptide ligand that links cMyb and MLL sequences was recently described; this study further illustrates the challenge in targeting an individual KIX cavity with low to medium molecular weight compounds. 17 In our previous studies, we used the computational algorithm AlphaSpace 18 to topographically map protein surfaces and design natural and nonnatural side chains on peptide mimics. AlphaSpace analysis suggested that several MLL residues do not optimally occupy the closest lying pockets on KIX (Figure 1B) and that nonnatural residues may be designed to capture cryptic pockets.…”

Section: ■ Introductionmentioning

confidence: 99%

Peptide Tethering: Pocket-Directed Fragment Screening for Peptidomimetic Inhibitor Discovery

et al. 2022

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Constrained peptides have proven to be a rich source of ligands for protein surfaces, but are often limited in their binding potency. Deployment of nonnatural side chains that access unoccupied crevices on the receptor surface offers a potential avenue to enhance binding affinity. We recently described a computational approach to create topographic maps of protein surfaces to guide the design of nonnatural side chains [J. Am. Chem. Soc. 2017, 139, 15560]. The computational method, AlphaSpace, was used to predict peptide ligands for the KIX domain of the p300/CBP coactivator. KIX has been the subject of numerous ligand discovery strategies, but potent inhibitors of its interaction with transcription factors remain difficult to access. Although the computational approach provided a significant enhancement in the binding affinity of the peptide, fine-tuning of nonnatural side chains required an experimental screening method. Here we implement a peptide-tethering strategy to screen fragments as nonnatural side chains on conformationally defined peptides. The combined computational–experimental approach offers a general framework for optimizing peptidomimetics as inhibitors of protein–protein interactions.

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“…CBP/p300 KIX inhibitor MybLL (Figure 2), which links the TADs of Myb, and MLL to form a sub-nM dual-site inhibitor of KIX (Joy et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Such large peptides are oftentimes difficult to advance to clinical studies due to several challenging pharmacokinetic and pharmacodynamic (PK/PD) properties, such as low stability and poor tissue distribution (Diao and Meibohm, 2013). Additionally, the most potent and selective peptide inhibitors are based on the relatively well-structured regions of the TAD when it is bound to the coactivator (Ramaswamy et al, 2018;Joy et al, 2021). Fuzzy TF interactions that have more limited structural formation are therefore not likely to benefit from this approach.…”

Section: Introductionmentioning

confidence: 99%

Drugging Fuzzy Complexes in Transcription

Su¹,

Henley²

2021

Front. Mol. Biosci.

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Transcription factors (TFs) are one of the most promising but underutilized classes of drug targets. The high degree of intrinsic disorder in both the structure and the interactions (i.e., “fuzziness”) of TFs is one of the most important challenges to be addressed in this context. Here, we discuss the impacts of fuzziness on transcription factor drug discovery, describing how disorder poses fundamental problems to the typical drug design, and screening approaches used for other classes of proteins such as receptors or enzymes. We then speculate on ways modern biophysical and chemical biology approaches could synergize to overcome many of these challenges by directly addressing the challenges imposed by TF disorder and fuzziness.

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A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb

Cited by 25 publications

References 54 publications

KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer

KIX domain determines a selective tumor-promoting role for EP300 and its vulnerability in small cell lung cancer

Peptide Tethering: Pocket-Directed Fragment Screening for Peptidomimetic Inhibitor Discovery

Drugging Fuzzy Complexes in Transcription

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