Chemistry

Faculty

Matthew Disney, PhD

Professor
Department of Chemistry
Florida Campus
Laboratory Website
disney@scripps.edu
(561) 228-2203

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Research Focus

The Disney group develops rational approaches to design selective therapeutics from only genome sequence. One of the major advantages that genome sequencing efforts potentially provides is advancing patient-specific therapies, yet such developments have been only sparsely reported. We have developed general approach to provide lead Targeted Therapeutics and Precise Medicines that target RNAs that cause disease broadly and include rare neuromuscular (muscular dystrophy), neurodegenerative (Alzheimer’s, ALS), infectious diseases as well as difficult-to-treat cancers (breast, pancreatic, prostate, and others), and infectious diseases that can emerge through seasonal exposures. Designed compounds have demonstrated activity in human derived cellular disease models as well as pre-clinical animal models of disease. We train the next-generation of scientists to ensure our work has an exponential impact in studying disease biology and leveraging it into making Precision Medicines.

To achieve these goals, we developed a proprietary platform dubbed Inforna over the past 13 years. It merges chemoinformatics and RNA structure to identify lead compounds that target an RNA of interest; that is, Inforna houses a database of RNA three dimensional motifs that bind small molecule medicines, identified via an experimental library-versus-library screen. The bioinformatics pipeline rapidly and accurately identifies disease-associated RNA sequences that adopt targetable three-dimensional folds by comparison to the database. This pipeline has been validated in various peer-review publications that demonstrated that the platform can be used to target RNAs that cause neuromuscular, neurodegenerative, and infectious diseases as well as difficult-to-treat cancers in pre-clinical animal models. Additionally, lead small molecule medicines can also be rapidly developed into compounds that recruit cellular nucleases to selectively destroy the RNAs that cause these diseases in a catalytic and substoichiometric manner (e.g. one molecule of the small molecule cleaves more than one molecule of the RNA target) coined RIBOTACs. Two of the major perceived concerns in the area of RNA-targeted small molecules are selectivity and potency. We have broadly demonstrated that these issues can be rapidly overcome via rational design and fragment assembly.

Key recent advances include:

(i) Sequence-based drug design across the human transcriptome to provide precision lead medicines

(ii) Small molecule cleavage of RNAs (RIBOTACS) in a catalytic and sub-stoichiometric manner via recruitment of cellular nucleases

(iii) Tools and technologies to study ligand binding capacity of RNAs across the transcriptome (Chem-CLIP and Ribo-SNAP)

(iv) Showing broad classes of known drugs target RNA and that their activity may be traced to targeting non-coding RNA

(v) Chemical biology approaches to understand RNA biology. We uncovered the mechanistic cause of Fragule X-Syndrome and Autism and also can define precisely the effect that non-coding RNAs have on the proteome.

(vi) Study druggability broadly. We have the ability to answer fundamental questions about how druggable the genome really is. Thus, we have launched the Druggable Transcriptome Project.

Education

Ph.D., Biophysical Chemistry, University of Rochester, 2003
M.S., Chemistry, University of Rochester, 1999
B.S., Chemistry, University of Maryland, College Park, 1997

Professional Experience

2010-2020 Professor, The Scripps Research Institute
2005-2010 Assistant Professor, University at Buffalo, The State University of New York
2002-2005 Postdoctoral Fellow, Swiss Federal Institute of Technology Zurich (ETH)

Awards & Professional Activities

2021: The ACS 2022 Nobel Laureate Signature Award for Graduate Education in Chemistry recognizes exceptional students and their advisors
2019: The Raymond and Beverly Sackler International Prize in Chemistry
2018: BioFlorida's Weaver H. Gaines Entrepreneur of the Year
2018: The Barry Cohen Prize, awarded by the Medicinal Chemistry Section of the Israel Chemical Society and Teva Pharmaceutical Industries.
2017: Scripps Florida Outstanding Mentor Award
2016: Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry
2015: NIH Director’s Pioneer Award
2015, 2016, 2017: Blavatnik Young Scientists Award Finalist
2014: David W. Robertson Award in Medicinal Chemistry. Awarded by the American Chemical Society’s Division of Medicinal Chemistry for having a primary role in the discovery of a novel therapeutic agents, targets, theoretical concepts in medicinal chemistry or drug discovery, and making a significant scientific discovery that enhances the field of medicinal chemistry.
2013: Excellence Award in the field of Research in Science and Technology. India-US Chamber of Commerce, Inc., South Florida.
2013: Eli Lilly Award in Biological Chemistry from American Chemical Society in recognition of outstanding research in biological chemistry of unusual merit and independence of thought and originality.
2012: David Gin Award in Carbohydrate Chemistry from the American Chemical Society in recognition of excellence in carbohydrate chemistry from a new investigator.
May 2010: University at Buffalo, Excellent Scholar, Young Investigator Award
May 2010-April 2015: Dreyfus Teacher-Scholar Award.
July 2008-June 2010: Research Corporation Cottrell Scholar Award
July 2007-June 2009: NYSTAR JD Watson Young Investigator Award
September 2005-August 2010: Camille and Henry Dreyfus New Faculty Award
June 2004-January 2005: Second Year Roche Foundation Postdoctoral Fellowship, Swiss Federal Institute of Technology (ETH, Zürich)
June 2003-May 2004: Roche Foundation Postdoctoral Fellowship, Swiss Federal Institute of Technology (ETH, Zürich)
2001-2002: Arnold Weissberger Memorial Fellow, University of Rochester
2000-2001: Elon Huntington Hooker Memorial Fellow, University of Rochester
1997-1999: Sherman-Clark Memorial Fellow, University of Rochester
1997: Eric A. Batista Award, University of Maryland at College Park. Award for most outstanding undergraduate research.
1995-1997: Howard Hughes Medical Institute Undergraduate Research Fellow, University of Maryland at College Park.

Selected References

Meyer SM, Williams CC, Akahori Y, Tanaka T, Aikawa H, Tong Y, Childs-Disney JL, Disney MD. Small molecule recognition of disease-relevant RNA structures. Chemical Society Reviews, (2020) doi: 10.1039/d0cs00560f.

Ursu A, Childs-Disney JL, Andrews RJ, O'Leary CA, Meyer SM, Angelbello AJ, Moss WN, Disney MD. Design of small molecules targeting RNA structure from sequence. Chemical Society Reviews, (2020), doi: 10.1039/d0cs00455c.

Haniff HS, Knerr L, Liu X, Crynen G, Boström J, Abegg D, Adibekian A, Lekah E, Wang KW, Cameron MD, Yildirim I, Lemurell M, Disney MD. Design of a small molecule that stimulates vascular endothelial growth factor A enabled by screening RNA fold-small molecule interactions. Nature Chemistry, (2020), doi: 10.1038/s41557-020-0514-4.

Benhamou RI, Vezina-Dawod S, Choudhary S, Won Wang K, Meyer SM, Yildirim I, Disney MD. Macrocyclization of a ligand targeting a toxic RNA dramatically improves potency. Chembiochem, (2020), doi: 10.1002/cbic.202000445.

Benhamou RI, Abe M, Choudhary S, Meyer SM, Angelbello AJ, Disney MD. Optimization of the linker domain in a dimeric compound that degrades an r(CUG) repeat expansion in cells. Journal of Medicinal Chemistry, (2020), 63:7827-7839. doi: 10.1021/acs.jmedchem.0c00558.

Angelbello AJ, Disney MD. A toxic RNA templates the synthesis of its own fluorogenic inhibitor by using a bio-orthogonal tetrazine ligation in cells and tissues. ACS Chemical Biology, (2020), 15:1820-1825. doi: 10.1021/acschembio.0c00417.

Ursu A, Childs-Disney JL, Angelbello AJ, Costales MG, Meyer SM, Disney MD. Gini coefficients as a single value metric to define chemical probe selectivity. ACS Chemical Biology, (2020), 15:2031-2040. doi: 10.1021/acschembio.0c00486.

Disney MD, Suresh BM, Benhamou RI, Childs-Disney JL. Progress toward the development of the small molecule equivalent of small interfering RNA. Current Opinions in Chemical Biology, (2020), 56:63-71. doi: 10.1016/j.cbpa.2020.01.001.

Haniff HS, Knerr L, Chen JL, Disney MD, Lightfoot HL. Target-directed approaches for screening small molecules against RNA targets. SLAS Discovery, (2020), 2472555220922802. doi: 10.1177/2472555220922802.

Chen JL, Zhang P, Abe M, Aikawa H, Zhang L, Frank AJ, Zembryski T, Hubbs C, Park H, Withka J, Steppan C, Rogers L, Cabral S, Pettersson M, Wager TT, Fountain MA, Rumbaugh G, Childs-Disney JL, Disney MD. Design, optimization, and study of small molecules that target Tau pre-mRNA and affect splicing. Journal of the American Chemical Society, (2020), 142:8706-8727. doi: 10.1021/jacs.0c00768.

Todd TW, McEachin ZT, Chew J, Burch AR, Jansen-West K, Tong J, Yue M, Song Y, Castanedes-Casey M, Kurti A, Dunmore JH, Fryer JD, Zhang YJ, San Millan B, Teijeira Bautista S, Arias M, Dickson D, Gendron TF, Sobrido MJ, Disney MD, Bassell GJ, Rossoll W, Petrucelli L. Hexanucleotide repeat expansions in c9FTD/ALS and SCA36 confer selective patterns of neurodegeneration in vivo. Cell Reports, (2020), 31:107616. doi: 10.1016/j.celrep.2020.107616.

Andrews RJ, Peterson JM, Haniff HS, Chen J, Williams C, Grefe M, Disney MD, Moss WN. An in silico map of the SARS-CoV-2 RNA structurome. bioRxiv, (2020), in press. doi: 10.1101/2020.04.17.045161.

Angelbello AJ, DeFeo ME, Glinkerman CM, Boger DL, Disney MD. Precise targeted cleavage of a r(CUG) repeat expansion in cells by using a small-molecule-deglycobleomycin conjugate. ACS Chemical Biology, (2020), 15:849-855. doi: 10.1021/acschembio.0c00036.

Liu X, Haniff HS, Childs-Disney JL, Shuster A, Aikawa H, Adibekian A, Disney MD. Targeted degradation of the oncogenic microRNA 17-92 cluster by structure-targeting ligands. Journal of the American Chemical Society, (2020), 142:6970-6982. doi: 10.1021/jacs.9b13159.

Costales MG, Childs-Disney JL, Haniff HS, Disney MD. How we think about targeting RNA with small molecules. Journal of Medicinal Chemistry, (2020), 63:8880-8900. doi: 10.1021/acs.jmedchem.9b01927.

Benhamou RI, Angelbello AJ, Andrews RJ, Wang ET, Moss WN, Disney MD. Structure-specific cleavage of an RNA repeat expansion with a dimeric small molecule is advantageous over sequence-specific recognition by an oligonucleotide. ACS Chemical Biology, (2020), 15:485-493. doi: 10.1021/acschembio.9b00958.

Benhamou RI, Angelbello AJ, Wang ET, Disney MD. A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways. Cell Chemical Biology, (2020), 27:223-231.e4. doi: 10.1016/j.chembiol.2020.01.003.

Costales MG, Aikawa H, Li Y, Childs-Disney JL, Abegg D, Hoch DG, Pradeep Velagapudi S, Nakai Y, Khan T, Wang KW, Yildirim I, Adibekian A, Wang ET, Disney MD. Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer. Proceedings from the National Academy of Sciences USA, (2020), 117:2406-2411. doi: 10.1073/pnas.1914286117.

Zhang P, Park HJ, Zhang J, Junn E, Andrews RJ, Velagapudi SP, Abegg D, Vishnu K, Costales MG, Childs-Disney JL, Adibekian A, Moss WN, Mouradian MM, Disney MD. Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA. Proceedings from the National Academy of Sciences USA, (2020), 117:1457-1467. doi: 10.1073/pnas.1905057117.