A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

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SUMMARY

Id helix-loop-helix (HLH) proteins (Id1–4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.

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Wojnarowicz et al., describe the identification, by an in silico screen, and characterization of a small molecule, AGX51, that targets Id proteins. AGX51 treatment of cells lead to Id protein degradation, cell cycle arrest, and reduced cell viability. AGX51 inhibited pathologic ocular neovascularization in mouse models, phenocopying genetic Id loss.

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Most cited references 41

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Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.

John C Shelley, Anuradha Cholleti, Leah Frye … (2007)

Epik is a computer program for predicting pK(a) values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pK(a) prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.

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Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution.

Jeremy Greenwood, David R. Calkins, Arron Sullivan … (2010)

Generating the appropriate protonation states of drug-like molecules in solution is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compounds requires a method for determining tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximise enrichment, the lowest energy tautomers must be determined from heterogeneous input, without over-enumerating unfavourable states. While computationally expensive, the density functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett-Taft methodology can very rapidly extrapolate substituent effects from model systems to drug-like molecules via the relationship between pK(T) and pK(a). Combining the two complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited number of measured pK(T) values, especially for the complicated heterocycles often favoured by medicinal chemists for their novelty and versatility. Several hundreds of pre-calculated tautomer energies and substituent pK(a) effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aqueous ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and experimental data. Recommendations are made for how to best incorporate tautomers in molecular design and virtual screening workflows.

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Prevalence of age-related maculopathy. The Beaver Dam Eye Study.

R. Klein, B Klein, K L Linton (1992)

The relationships of retinal drusen, retinal pigmentary abnormalities, and macular degeneration to age and sex were studied in 4926 people between the ages of 43 and 86 years who participated in the Beaver Dam Eye Study. The presence and severity of various characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. One or more drusen were present in the macular area of at least 1 eye in 95.5% of the population. People 75 years of age or older had significantly higher frequencies (P less than 0.01) of the following characteristics than people 43 to 54 years of age: larger sized drusen (greater than or equal to 125 microns, 24.0% versus 1.9%), soft indistinct drusen (23.0% versus 2.1%), retinal pigment abnormalities (26.6% versus 7.3%), exudative macular degeneration (5.2% versus 0.1%), and geographic atrophy (2.0% versus 0%). These data indicate signs of age-related maculopathy are common in people 75 years of age or older and may pose a substantial public health problem.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 20 November 2019

Publication date (Print): 01 October 2019

Publication date PMC-release: 06 December 2019

Volume: 29

Issue: 1

Pages: 62-75.e7

Affiliations

[1 ]Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[2 ]Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

[3 ]Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA

[4 ]Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA

[5 ]Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[6 ]Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[7 ]Alliance Protein Laboratories, a Division of KBI Biopharma, San Diego, CA 92121, USA

[8 ]Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[9 ]Tosk, Inc., Mountain View, CA 94043, USA

[10 ]Ophthalmic Consultants of Long Island, Lynbrook, NY 11563, USA

[11 ]Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA

[12 ]Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[13 ]Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[14 ]Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA

[15 ]Department of Pediatrics, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA

[16 ]Lead Contact

Author notes

AUTHOR CONTRIBUTIONS

Conceptualization, P.M.W., W.A.G., A.J.D., L.N., and R.B.; Methodology, P.M.W., R.L.e.S., A.K., Y.G., O.O., T.A., W.A.G., G.S., J.C., R.C.H., J.D.C., N.P., and R.B.; Formal Analysis, P.M.W., R.L.e.S., S.-H.C., T.A., S.K.A., R.K.S., J.P., and R.C.H.; Investigation, P.M.W., R.L.e.S., M.O., S.B.L., Y.C., A.K., S.-H.C., B.D., M.G.E., R.S., M.G.-C., S.X., R.K., Y.G., M.A.M., G.Y., T.A., S.K.A., R.S., and J.P.; Resources, O.O. and G.Y.; Writing – Original Draft, P.M.W. and R.B.; Writing – Review & Editing, P.M.W., A.J.D., M.G.E., and R.B.; Visualization, P.M.W., R.L.e.S., S.B.L., S.-H.C., T.A., S.K.A., R.C.H., and R.B.; Supervision, O.O., A.I., J.D.C., N.P., A.L., P.A.C., and R.B.; Funding Acquisition, A.I., A.J.D., J.D.C., and R.B.

[* ]Correspondence: benezrar@ 123456mskcc.org

Article

Manuscript ID: NIHMS1543421

DOI: 10.1016/j.celrep.2019.08.073

PMC ID: 6896334

PubMed ID: 31577956

SO-VID: 9e666e4b-115c-4179-ac07-63e8e8a0be42

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

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SUMMARY

Graphical Abstract

In Brief

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Claudins

Most cited references 41

Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution.

Prevalence of age-related maculopathy. The Beaver Dam Eye Study.

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