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

Paulina M. Wojnarowicz; Raquel Lima e Silva; Masayuki Ohnaka; Sang Bae Lee; Yvette Chin; Anita Kulukian; Sung Hee Chang; Bina Desai; Marta Garcia Escolano; Riddhi Shah; Marta Garcia-Cao; Sijia Xu; Rashmi Kadam; Yehuda Goldgur; Meredith A. Miller; Ouathek Ouerfelli; Guangli Yang; Tsutomu Arakawa; Steven K. Albanese; William A. Garland; Glenn Stoller; Jaideep Chaudhary; Larry Norton; Rajesh Kumar Soni; John Philip; Ronald C. Hendrickson; Antonio Iavarone; Andrew J. Dannenberg; John D. Chodera; Nikola Pavletich; Anna Lasorella; Peter A. Campochiaro; Robert Benezra

doi:10.1016/j.celrep.2019.08.073

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

Paulina M. Wojnarowicz, Raquel Lima e Silva, Masayuki Ohnaka, Sang Bae Lee, Yvette Chin, Anita Kulukian, Sung Hee Chang, Bina Desai, Marta Garcia Escolano, Riddhi Shah, Marta Garcia-Cao, Sijia Xu, Rashmi Kadam, Yehuda Goldgur, Meredith A. Miller, Ouathek Ouerfelli, Guangli Yang, Tsutomu Arakawa, Steven K. Albanese, William A. GarlandGlenn Stoller, Jaideep Chaudhary, Larry Norton, Rajesh Kumar Soni, John Philip, Ronald C. Hendrickson, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Peter A. Campochiaro, Robert Benezra

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	62-75.e7
Journal	Cell Reports
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2019.08.073
State	Published - Oct 1 2019

Keywords

Id proteins
angiogenesis
macular degeneration
protein-protein interactions
retinopathy of prematurity

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2019.08.073

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Wojnarowicz, P. M., Lima e Silva, R., Ohnaka, M., Lee, S. B., Chin, Y., Kulukian, A., Chang, S. H., Desai, B., Garcia Escolano, M., Shah, R., Garcia-Cao, M., Xu, S., Kadam, R., Goldgur, Y., Miller, M. A., Ouerfelli, O., Yang, G., Arakawa, T., Albanese, S. K., ... Benezra, R. (2019). A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization. Cell Reports, 29(1), 62-75.e7. https://doi.org/10.1016/j.celrep.2019.08.073

Wojnarowicz, PM, Lima e Silva, R, Ohnaka, M, Lee, SB, Chin, Y, Kulukian, A, Chang, SH, Desai, B, Garcia Escolano, M, Shah, R, Garcia-Cao, M, Xu, S, Kadam, R, Goldgur, Y, Miller, MA, Ouerfelli, O, Yang, G, Arakawa, T, Albanese, SK, Garland, WA, Stoller, G, Chaudhary, J, Norton, L, Soni, RK, Philip, J, Hendrickson, RC, Iavarone, A, Dannenberg, AJ, Chodera, JD, Pavletich, N, Lasorella, A, Campochiaro, PA & Benezra, R 2019, 'A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization', Cell Reports, vol. 29, no. 1, pp. 62-75.e7. https://doi.org/10.1016/j.celrep.2019.08.073

@article{fe6713faeeb64748bbbf7cd2945f2ef1,

title = "A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization",

abstract = "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.",

keywords = "Id proteins, angiogenesis, macular degeneration, protein-protein interactions, retinopathy of prematurity",

author = "Wojnarowicz, {Paulina M.} and {Lima e Silva}, Raquel and Masayuki Ohnaka and Lee, {Sang Bae} and Yvette Chin and Anita Kulukian and Chang, {Sung Hee} and Bina Desai and {Garcia Escolano}, Marta and Riddhi Shah and Marta Garcia-Cao and Sijia Xu and Rashmi Kadam and Yehuda Goldgur and Miller, {Meredith A.} and Ouathek Ouerfelli and Guangli Yang and Tsutomu Arakawa and Albanese, {Steven K.} and Garland, {William A.} and Glenn Stoller and Jaideep Chaudhary and Larry Norton and Soni, {Rajesh Kumar} and John Philip and Hendrickson, {Ronald C.} and Antonio Iavarone and Dannenberg, {Andrew J.} and Chodera, {John D.} and Nikola Pavletich and Anna Lasorella and Campochiaro, {Peter A.} and Robert Benezra",

note = "Funding Information: The authors are grateful to members of the Benezra Lab, past and present, for helpful discussions throughout the course of this work. We are also grateful to Andrea Rizzi for additional supportive modeling work of AGX51 interactions and Drs. Gary Cook and Gary Novack for expert guidance on the ophthalmic studies. We thank Elisa de Stanchina and the MSKCC Antitumor Assessment Core Facility for assistance with pharmacokinetic and bioavailability assays, Nicholas Socci and the MSKCC Bioinformatics Core Facility for additional statistical analyses, and Jorge Gandara of the Weill Cornell Medical College Microbiome Core for assistance with the GloMax instrument. For expert guidance in implementing and executing the NanoBRET assay, we wish to thank Dan McKay and William Forrester at Novartis and James Vasta at Promega. R.B. and J.D.C. gratefully acknowledge support from the Sloan Kettering Institute and NIH grant P30 CA008748 . R.B. is also supported by grants from the NCI ( PO1 CA094060 ) and The Breast Cancer Research Foundation . A.J.D. is supported by funding from The Breast Cancer Research Foundation . S.K.A. was supported by the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences . Work was partially supported by 1R43CA150448-01 from NCI/NIH to W.A.G. and NIH grants to A.I. ( R01CA101644 and R01CA131126 ). M.G.-C. was funded by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). P.M.W. is a recipient of a Postdoctoral Training Award from the Fonds de Recherche du Quebec-Sante; (FRQS). M.G.E. was supported by fellowships issued by the Valencian Government of Spain (GVA) and the European Social Fund ( ACIF/2018/004 and BEFPI/2018/029 ). Financial support was also provided by Angiogenex, Inc. to the R.B. Laboratory. Funding Information: The authors are grateful to members of the Benezra Lab, past and present, for helpful discussions throughout the course of this work. We are also grateful to Andrea Rizzi for additional supportive modeling work of AGX51 interactions and Drs. Gary Cook and Gary Novack for expert guidance on the ophthalmic studies. We thank Elisa de Stanchina and the MSKCC Antitumor Assessment Core Facility for assistance with pharmacokinetic and bioavailability assays, Nicholas Socci and the MSKCC Bioinformatics Core Facility for additional statistical analyses, and Jorge Gandara of the Weill Cornell Medical College Microbiome Core for assistance with the GloMax instrument. For expert guidance in implementing and executing the NanoBRET assay, we wish to thank Dan McKay and William Forrester at Novartis and James Vasta at Promega. R.B. and J.D.C. gratefully acknowledge support from the Sloan Kettering Institute and NIH grant P30 CA008748. R.B. is also supported by grants from the NCI (PO1 CA094060) and The Breast Cancer Research Foundation. A.J.D. is supported by funding from The Breast Cancer Research Foundation. S.K.A. was supported by the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences. Work was partially supported by 1R43CA150448-01 from NCI/NIH to W.A.G. and NIH grants to A.I. (R01CA101644 and R01CA131126). M.G.-C. was funded by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). P.M.W. is a recipient of a Postdoctoral Training Award from the Fonds de Recherche du Quebec-Sante; (FRQS). M.G.E. was supported by fellowships issued by the Valencian Government of Spain (GVA) and the European Social Fund (ACIF/2018/004 and BEFPI/2018/029). Financial support was also provided by Angiogenex, Inc. to the R.B. Laboratory. 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. R.B. W.A.G. J.C. and G.S. own shares of Angiogenex, Inc. which holds the patent for the use and development of AGX51. R.B. is the chief scientific officer of Angiogenex, Inc. and a board member, both positions unpaid. G.Y. is listed as an inventor on patents that were filed by MSKCC. O.O. is listed as an inventor and receives royalties from patents that were filed by MSKCC. O.O. is an unpaid member of the SAB of Angiogenex, Inc. and owns shares in Angiogenex, Inc. J.D.C. was on the Scientific Advisory Board for Schr{\"o}dinger during part of this research and now serves on the Scientific Advisory Board of OpenEye Scientific. Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.celrep.2019.08.073",

language = "English (US)",

volume = "29",

pages = "62--75.e7",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization

AU - Wojnarowicz, Paulina M.

AU - Lima e Silva, Raquel

AU - Ohnaka, Masayuki

AU - Lee, Sang Bae

AU - Chin, Yvette

AU - Kulukian, Anita

AU - Chang, Sung Hee

AU - Desai, Bina

AU - Garcia Escolano, Marta

AU - Shah, Riddhi

AU - Garcia-Cao, Marta

AU - Xu, Sijia

AU - Kadam, Rashmi

AU - Goldgur, Yehuda

AU - Miller, Meredith A.

AU - Ouerfelli, Ouathek

AU - Yang, Guangli

AU - Arakawa, Tsutomu

AU - Albanese, Steven K.

AU - Garland, William A.

AU - Stoller, Glenn

AU - Chaudhary, Jaideep

AU - Norton, Larry

AU - Soni, Rajesh Kumar

AU - Philip, John

AU - Hendrickson, Ronald C.

AU - Iavarone, Antonio

AU - Dannenberg, Andrew J.

AU - Chodera, John D.

AU - Pavletich, Nikola

AU - Lasorella, Anna

AU - Campochiaro, Peter A.

AU - Benezra, Robert

N1 - Funding Information: The authors are grateful to members of the Benezra Lab, past and present, for helpful discussions throughout the course of this work. We are also grateful to Andrea Rizzi for additional supportive modeling work of AGX51 interactions and Drs. Gary Cook and Gary Novack for expert guidance on the ophthalmic studies. We thank Elisa de Stanchina and the MSKCC Antitumor Assessment Core Facility for assistance with pharmacokinetic and bioavailability assays, Nicholas Socci and the MSKCC Bioinformatics Core Facility for additional statistical analyses, and Jorge Gandara of the Weill Cornell Medical College Microbiome Core for assistance with the GloMax instrument. For expert guidance in implementing and executing the NanoBRET assay, we wish to thank Dan McKay and William Forrester at Novartis and James Vasta at Promega. R.B. and J.D.C. gratefully acknowledge support from the Sloan Kettering Institute and NIH grant P30 CA008748 . R.B. is also supported by grants from the NCI ( PO1 CA094060 ) and The Breast Cancer Research Foundation . A.J.D. is supported by funding from The Breast Cancer Research Foundation . S.K.A. was supported by the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences . Work was partially supported by 1R43CA150448-01 from NCI/NIH to W.A.G. and NIH grants to A.I. ( R01CA101644 and R01CA131126 ). M.G.-C. was funded by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). P.M.W. is a recipient of a Postdoctoral Training Award from the Fonds de Recherche du Quebec-Sante; (FRQS). M.G.E. was supported by fellowships issued by the Valencian Government of Spain (GVA) and the European Social Fund ( ACIF/2018/004 and BEFPI/2018/029 ). Financial support was also provided by Angiogenex, Inc. to the R.B. Laboratory. Funding Information: The authors are grateful to members of the Benezra Lab, past and present, for helpful discussions throughout the course of this work. We are also grateful to Andrea Rizzi for additional supportive modeling work of AGX51 interactions and Drs. Gary Cook and Gary Novack for expert guidance on the ophthalmic studies. We thank Elisa de Stanchina and the MSKCC Antitumor Assessment Core Facility for assistance with pharmacokinetic and bioavailability assays, Nicholas Socci and the MSKCC Bioinformatics Core Facility for additional statistical analyses, and Jorge Gandara of the Weill Cornell Medical College Microbiome Core for assistance with the GloMax instrument. For expert guidance in implementing and executing the NanoBRET assay, we wish to thank Dan McKay and William Forrester at Novartis and James Vasta at Promega. R.B. and J.D.C. gratefully acknowledge support from the Sloan Kettering Institute and NIH grant P30 CA008748. R.B. is also supported by grants from the NCI (PO1 CA094060) and The Breast Cancer Research Foundation. A.J.D. is supported by funding from The Breast Cancer Research Foundation. S.K.A. was supported by the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences. Work was partially supported by 1R43CA150448-01 from NCI/NIH to W.A.G. and NIH grants to A.I. (R01CA101644 and R01CA131126). M.G.-C. was funded by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). P.M.W. is a recipient of a Postdoctoral Training Award from the Fonds de Recherche du Quebec-Sante; (FRQS). M.G.E. was supported by fellowships issued by the Valencian Government of Spain (GVA) and the European Social Fund (ACIF/2018/004 and BEFPI/2018/029). Financial support was also provided by Angiogenex, Inc. to the R.B. Laboratory. 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. R.B. W.A.G. J.C. and G.S. own shares of Angiogenex, Inc. which holds the patent for the use and development of AGX51. R.B. is the chief scientific officer of Angiogenex, Inc. and a board member, both positions unpaid. G.Y. is listed as an inventor on patents that were filed by MSKCC. O.O. is listed as an inventor and receives royalties from patents that were filed by MSKCC. O.O. is an unpaid member of the SAB of Angiogenex, Inc. and owns shares in Angiogenex, Inc. J.D.C. was on the Scientific Advisory Board for Schrödinger during part of this research and now serves on the Scientific Advisory Board of OpenEye Scientific. Publisher Copyright: © 2019 The Author(s)

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Id proteins

KW - angiogenesis

KW - macular degeneration

KW - protein-protein interactions

KW - retinopathy of prematurity

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U2 - 10.1016/j.celrep.2019.08.073

DO - 10.1016/j.celrep.2019.08.073

M3 - Article

C2 - 31577956

AN - SCOPUS:85072314164

VL - 29

SP - 62-75.e7

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 1

ER -

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

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