Genie in a bottle: controlled release helps tame natural polypharmacology?

Ability to faithfully report drug-target interactions constitutes a major critical parameter in preclinical/clinical settings. Yet the assessment of target engagement remains challenging, particularly for promiscuous and/or polypharmacologic ligands. Drawing from our improved insights into native electrophile signaling and emerging technologies that profile and interrogate these non-enzyme-assisted signaling subsystems, we posit that 'trained' polypharmocologic covalent inhibitors can be designed. Accumulating evidence indicates that electrophile-modified states at fractional occupancy can alter cell fate. Thus, by understanding sensing preferences and ligandable regions favored by the natural electrophilic signals at individual protein-ligand resolution, we can better evaluate target engagement and develop a function-guided understanding of polypharmacology.

[1]  B. Aggarwal,et al.  Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials , 2012, The AAPS Journal.

[2]  Juanita Lopez,et al.  Combine and conquer: challenges for targeted therapy combinations in early phase trials , 2017, Nature Reviews Clinical Oncology.

[3]  T. Kensler,et al.  KEAP1 and done? Targeting the NRF2 pathway with sulforaphane , 2017, Trends in food science & technology.

[4]  R. H. Levin,et al.  The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. , 1965, Blood.

[5]  J. Hayes,et al.  The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. , 2014, Trends in biochemical sciences.

[6]  John T. Powers,et al.  Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors , 2010, Nature.

[7]  Jing-xin Pan,et al.  Resistance to arsenic trioxide and retinoic acid therapy in acute promyelocytic leukemia , 2017, Annals of Hematology.

[8]  Benjamin F. Cravatt,et al.  A roadmap to evaluate the proteome-wide selectivity of covalent kinase inhibitors , 2014, Nature chemical biology.

[9]  E. Weerapana,et al.  Identifying Functional Cysteine Residues in the Mitochondria. , 2017, ACS chemical biology.

[10]  F. Pagnini,et al.  Comparison of Dasatinib, Nilotinib, and Imatinib in the Treatment of Chronic Myeloid Leukemia , 2016, Journal of cellular physiology.

[11]  J. Baynes,et al.  Succination of Proteins by Fumarate , 2008, Annals of the New York Academy of Sciences.

[12]  A. Petrelli,et al.  Polypharmacological Kinase Inhibitors: New Hopes for Cancer Therapy , 2012 .

[13]  Paul H. Huang,et al.  b-TrCP 1 Is a Vacillatory Regulator of Wnt Signaling Graphical Abstract Highlights , 2017 .

[14]  B. Cravatt,et al.  Chemical proteomic map of dimethyl fumarate–sensitive cysteines in primary human T cells , 2016, Science Signaling.

[15]  David Basanta,et al.  Exploiting evolution to treat drug resistance: combination therapy and the double bind. , 2011, Molecular pharmaceutics.

[16]  G. Superti-Furga,et al.  Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth , 2016, Leukemia.

[17]  B. Freeman,et al.  Electrophilic fatty acid nitroalkenes regulate Nrf2 and NF-κB signaling:A medicinal chemistry investigation of structure-function relationships , 2018, Scientific Reports.

[18]  Daniel A. Urul,et al.  Precision Electrophile Tagging in Caenorhabditis elegans , 2017, Biochemistry.

[19]  Benjamin F. Cravatt,et al.  A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles , 2013, Nature Methods.

[20]  K. Shokat,et al.  Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases , 2008, Nature chemical biology.

[21]  M. Long,et al.  Redox Signaling by Reactive Electrophiles and Oxidants. , 2018, Chemical reviews.

[22]  A. Jimeno,et al.  Inhibition of EphB4–Ephrin-B2 Signaling Enhances Response to Cetuximab–Radiation Therapy in Head and Neck Cancers , 2018, Clinical Cancer Research.

[23]  M. Baccarani,et al.  Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056) , 2014 .

[24]  Herman Yeger,et al.  Combination therapy in combating cancer , 2017, Oncotarget.

[25]  Hongqiao Zhang,et al.  4-hydroxynonenal-mediated signaling and aging. , 2017, Free radical biology & medicine.

[26]  Y. Aye,et al.  Privileged Electrophile Sensors: A Resource for Covalent Drug Development. , 2017, Cell chemical biology.

[27]  N. Gray,et al.  Kinase inhibitors: the road ahead , 2018, Nature Reviews Drug Discovery.

[28]  Chi-Ping Day,et al.  Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges , 2015, Cell.

[29]  R. Larson,et al.  Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. , 2018, Blood advances.

[30]  Q. Lin,et al.  A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling. , 2015, Journal of the American Chemical Society.

[31]  Antonio Lavecchia,et al.  In silico methods to address polypharmacology: current status, applications and future perspectives. , 2016, Drug discovery today.

[32]  Ewgenij Proschak,et al.  Polypharmacology by Design: A Medicinal Chemist's Perspective on Multitargeting Compounds. , 2018, Journal of medicinal chemistry.

[33]  S. Zhang,et al.  Ube2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses , 2018, ACS central science.

[34]  Yi Zhao,et al.  T-REX on-demand redox targeting in live cells , 2016, Nature Protocols.

[35]  D. Wishart.  Emerging applications of metabolomics in drug discovery and precision medicine , 2016, Nature Reviews Drug Discovery.

[36]  Suneet Shukla,et al.  Sunitinib (Sutent, SU11248), a Small-Molecule Receptor Tyrosine Kinase Inhibitor, Blocks Function of the ATP-Binding Cassette (ABC) Transporters P-Glycoprotein (ABCB1) and ABCG2 , 2009, Drug Metabolism and Disposition.

[37]  Marcus J C Long,et al.  Proteomics and Beyond: Cell Decision-Making Shaped by Reactive Electrophiles. , 2019, Trends in biochemical sciences.

[38]  Antonio Ayala,et al.  Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal , 2014, Oxidative medicine and cellular longevity.

[39]  P. Nissen,et al.  Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases , 2018, Nature Communications.

[40]  M. Meyerson,et al.  Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer , 2015, ACS chemical biology.

[41]  M. Ratain,et al.  Opportunities and challenges in the development of experimental drug combinations for cancer. , 2011, Journal of the National Cancer Institute.

[42]  Peter A. Calabresi,et al.  Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity , 2018, Science.

[43]  A. Phillips,et al.  Life expectancy living with HIV: recent estimates and future implications , 2013, Current opinion in infectious diseases.

[44]  R. Sobel,et al.  Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2 , 2016, Proceedings of the National Academy of Sciences.

[45]  John P. Overington,et al.  Structural and Functional View of Polypharmacology , 2016, bioRxiv.

[46]  Yi Zhao,et al.  Akt3 is a privileged first responder in isozyme-specific electrophile response. , 2017, Nature chemical biology.

[47]  Ying Chen,et al.  Chemoproteomic profiling of protein modifications by lipid-derived electrophiles. , 2016, Current opinion in chemical biology.

[48]  C. Ambrosone,et al.  Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the United States. , 2013, Journal of functional foods.

[49]  K. Shokat,et al.  Targeting the cancer kinome through polypharmacology , 2010, Nature Reviews Cancer.