Stephen Neidle

Last updated

Professor Stephen Neidle is a British X-ray crystallographer, chemist and drug designer working at the UCL School of Pharmacy. His area of scientific research has been in nucleic acid structure and recognition, and the research topic of quadruplexes.

Contents

Early life, education and career

Stephen Neidle was born in London and educated at Hendon County Grammar School. He received a bachelor's degree in chemistry, a Ph.D. in X-ray crystallography supervised by Donald Rogers (during which he solved the structure of streptomycin). [1] and a D.Sc. in 1995, all from Imperial College London. [2] He received an ICI Fellowship for X-ray crystallographic studies with Michael B. Hursthouse at Queen Mary University of London working on natural products and pyrrole-based compounds. Subsequently he moved to the Biophysics Department, King's College London to work on the single crystal X-ray structures of nucleic acid and nucleic acid-drug complexes and was awarded a CRC (now CRUK) Career Development Award while being a Senior Research Fellow at King's College London. [2]

He moved to the Institute of Cancer Research, Sutton as a CRC (now CRUK) Life Fellow to head the Biomolecular Structure Unit, working on anticancer drug development, on the study of their complexes with nucleic acid and protein targets of clinical importance. This work lead to a high-resolution structure of a DNA quadruplex [3] and structural studies on protein-drug complexes, such as that of diaphorase with CB1954 (ChesterBeatty 1954), an anticancer prodrug. Neidle was appointed to the Chair of Biophysics at ICR in 1990, and then made Academic Dean 1997–2002. [4] He later moved to Institute of Cancer Research, Fulham Road [5] and subsequently to the first Chair of Chemical Biology at UCL School of Pharmacy. He is now Emeritus Professor of Chemical Biology at the University College London and CRUK Professorial Fellow. [2]

Research

Neidle has worked in the area of academic drug discovery and has been heavily involved in the development of drugs which recognise DNA. One of the anticancer drugs which he has been involved in developing has been abiraterone, which is used in the treatment of advanced prostate cancer. [6] More recently he and his collaborators played a key role [7] in the design of a novel antibiotic, ridinilazole, which has recently been assessed in phase III clinical trials for the treatment of Clostridioides difficile infections. [8]

His current research interests centre on the development of novel therapeutic agents using fundamental aspects of the chemistry and biology of nucleic acid structure and its recognition by small molecules, using this to computationally design improved drugs with enhanced specificity. He has led in the study of G-quadruplex nucleic acids as therapeutic targets, [9] [10] [11] [12] [13] especially focussing on their structure and recognition, using structural, chemical and biological approach in an integrated multidisciplinary approach. Most recently his research group has designed several compounds showing high activity in vitro and in vivo against human cancers, in particular pancreatic cancer. [14] [15] UCL Business have been instrumental in licensing these new experimental drugs in January 2022. These are being developed by Qualigen Therapeutics Inc in San Diego. [16] In January 2023 the USA Food and Drug Administration approved the lead compound QN-302 for Orphan Drug designation in pancreatic cancer. In July 2023 Qualigen Therapeutics Inc received IND clearance from the FDA to initiate a Phase 1 clinical trial of QN-302 for the treatment of advanced or metastatic solid tumors.

Neidle has published over 500 papers and reviews, [2] 14 patents, edited nine books and has written four books on nucleic acid structure, drug-DNA interactions and cancer drug discovery. His current h-index is 116 (Google Scholar). [17] He was European editor of Bioorganic & Medicinal Chemistry Letters and became its editor-in-chief 2019-2021. [18]

Family

Neidle is Jewish. He is married to Andrea, a copywriter. His children include Dan Neidle, formerly head of UK tax at Clifford Chance. [19]

Honours and awards

Neidle has received various national and international awards for his work, including: [20]

Related Research Articles

<span class="mw-page-title-main">Drug discovery</span> Pharmaceutical procedure

In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered.

<span class="mw-page-title-main">Antimetabolite</span> Chemical that inhibits the use of a metabolite

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used in chemotherapy for cancer.

<span class="mw-page-title-main">G-quadruplex</span> Structure in molecular biology

In molecular biology, G-quadruplex secondary structures (G4) are formed in nucleic acids by sequences that are rich in guanine. They are helical in shape and contain guanine tetrads that can form from one, two or four strands. The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of multiple genes, both in microbes and across vertebrates including oncogenes in humans. Four guanine bases can associate through Hoogsteen hydrogen bonding to form a square planar structure called a guanine tetrad, and two or more guanine tetrads can stack on top of each other to form a G-quadruplex.

<span class="mw-page-title-main">Deoxycytidine kinase</span> Protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

In biochemistry, two biopolymers are antiparallel if they run parallel to each other but with opposite directionality (alignments). An example is the two complementary strands of a DNA double helix, which run in opposite directions alongside each other.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

<span class="mw-page-title-main">Tachykinin receptor 1</span> Protein-coding gene in the species Homo sapiens

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

<span class="mw-page-title-main">Stephen J. Lippard</span> American chemist

Stephen James Lippard is the Arthur Amos Noyes Emeritus Professor of Chemistry at the Massachusetts Institute of Technology. He is considered one of the founders of bioinorganic chemistry, studying the interactions of nonliving substances such as metals with biological systems. He is also considered a founder of metalloneurochemistry, the study of metal ions and their effects in the brain and nervous system. He has done pioneering work in understanding protein structure and synthesis, the enzymatic functions of methane monooxygenase (MMO), and the mechanisms of cisplatin anticancer drugs. His work has applications for the treatment of cancer, for bioremediation of the environment, and for the development of synthetic methanol-based fuels.

<span class="mw-page-title-main">8-Carboxamidocyclazocine</span> Opioid agonist drug

8-Carboxamidocyclazocine (8-CAC) is an opioid analgesic drug related to cyclazocine, discovered by medicinal chemist Mark P. Wentland and co-workers in Cogswell Laboratory at Rensselaer Polytechnic Institute. Similarly to cyclazocine, 8-CAC acts as an agonist at both the μ- and κ-opioid receptors, but has a much longer duration of action than cyclazocine, and does not have μ antagonist activity. Unexpectedly, it was discovered that the phenolic hydroxyl group of cyclazocine could be replaced by a carboxamido group with only slight loss of potency at opioid receptors, and this discovery has subsequently been used to develop many novel opioid derivatives where the phenolic hydroxy group has been replaced by either carboxamide or a variety of larger groups. Due to their strong κ-opioid agonist activity, these drugs are not suited for use as analgesics in humans, but have instead been researched as potential drugs for the treatment of cocaine addiction.

Twisted intercalating nucleic acid (TINA) is a nucleic acid molecule that, when added to triplex-forming oligonucleotides (TFOs), stabilizes Hoogsteen triplex DNA formation from double-stranded DNA (dsDNA) and TFOs. Its ability to twist around a triple bond increases ease of intercalation within double stranded DNA in order to form triplex DNA. Certain configurations have been shown to stabilize Watson-Crick antiparallel duplex DNA. TINA-DNA primers have been shown to increase the specificity of binding in PCR. The use of TINA insertions in G-quadruplexes has also been shown to enhance anti-HIV-1 activity. TINA stabilized PT demonstrates improved sensitivity and specificity of DNA based clinical diagnostic assays.

<span class="mw-page-title-main">Shankar Balasubramanian</span> Indian-born British chemist

Sir Shankar Balasubramanian is an Indian-born British chemist and Herchel Smith Professor of Medicinal Chemistry in the Department of Chemistry at the University of Cambridge, Senior Group Leader at the Cancer Research UK Cambridge Institute and Fellow of Trinity College, Cambridge. He is recognised for his contributions in the field of nucleic acids. He is scientific founder of Solexa and biomodal.

Shantanu Chowdhury is an Indian structural biologist and a professor at Institute of Genomics and Integrative Biology of the Council of Scientific and Industrial Research. He is known for developing a mechanism for gene regulation mediated by DNA Secondary-Structure in diverse cellular contexts. An elected fellow of the National Academy of Sciences, India, he is a recipient of the National Bioscience Award for Career Development of the Department of Biotechnology in 2010. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards, in 2012, for his contributions to biological sciences.

<span class="mw-page-title-main">Santanu Bhattacharya</span> Indian chemical biologist

Santanu Bhattacharya is an Indian chemical biologist and former professor at the Indian Institute of Science. At, present he is the Director of the Indian Institute of Science Education and Research, Tirupati (IISER-Tirupati). He is known for his studies of unnatural amino acids, oligopeptides, designed and natural lipids, gene delivery vehicles, hydro- and organogels, molecular bioanalytic sensors, G-quadruplex DNA binding molecular therapeutics, and biologically active natural product mimics and is an elected fellow of the Indian National Science Academy The World Academy of Sciences and the Indian Academy of Sciences The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards, in 2003, for his contributions to chemical sciences. He is also a recipient of the National Bioscience Award for Career Development of the Department of Biotechnology (2002) and the TWAS Prize (2010).

<span class="mw-page-title-main">Distamycin</span> Chemical compound

Distamycin is a polyamide-antibiotic, which acts as a minor groove binder, binding to the small furrow of the double helix.

Mark S. Cushman is an American chemist, whose primary research is in the area of medicinal chemistry. He completed his pre-pharmacy studies at Fresno State College (now California State University, Fresno) in 1965. He then attended the University of California San Francisco (as a University of California Regents Scholar), earning a Pharm.D. in 1969 and a Ph.D. in Medicinal Chemistry in 1973. Thereafter, he performed postdoctoral training in the laboratory of George Büchi, Ph.D., at the Massachusetts Institute of Technology (MIT). There, his research focused on the discovery and development of new synthetic methodologies, and the isolation and structural characterization of mycotoxins from Aspergillus niger. In 1975, he joined the Department of Medicinal Chemistry and Molecular Pharmacology (at the time, Department of Medicinal Chemistry and Pharmacognosy) at Purdue University. From 1983 to 1984, Prof. Cushman was a Senior Fulbright Scholar at Munich Technical University working in the laboratory of Professor Adelbert Bacher. His sabbatical work dealt with the design and synthesis of probes to elucidate key aspects of the biosynthesis of riboflavin (vitamin B2). Currently he holds the rank of Distinguished Professor Emeritus of Medicinal Chemistry at Purdue University. He has mentored 40 graduate students, 59 postdoctoral researchers, and 5 visiting scholars. He has published 348 papers and holds 41 patents. His work has ~17,000 citations with an h-index of 69. His most cited papers had 471, 403, and 299 citations as of August 2021. He has made seminal contributions to the fields of synthetic and medicinal chemistry including the development of new synthetic methodologies, the synthesis of natural products, and the preparation of antivirals, antibacterials, and anticancer agents, and mechanism probes to understand the function of over thirty macromolecular targets. One of his main scientific contributions is the development of the indenoisoquinolines, molecules that inhibit the action of toposiomerase I (Top1) and stabilize the G-quadruplex in the Myc promoter. Three indenoisoquinolines designed and synthesized by his research group at Purdue University [indotecan (LMP 400), indimitecan (LMP 776), and LMP 744] demonstrated potent anticancer activity in vivo and have completed phase I clinical trials at the National Institutes of Health.

RNA-targeting small molecules represent a class of small molecules, organic compounds with traditional drug properties that can bind to RNA secondary or tertiary structures and alter translation patterns, localization, and degradation.

i-motif DNA, short for intercalated-motif DNA, are cytosine-rich four-stranded quadruplex DNA structures, similar to the G-quadruplex structures that are formed in guanine-rich regions of DNA.

<span class="mw-page-title-main">Guanine tetrad</span> Structure in molecular biology

In molecular biology, a guanine tetrad is a structure composed of four guanine bases in a square planar array. They most prominently contribute to the structure of G-quadruplexes, where their hydrogen bonding stabilizes the structure. Usually, there are at least two guanine tetrads in a G-quadruplex, and they often feature Hoogsteen-style hydrogen bonding.

Katherine Seley-Radtke is an American medicinal chemist who specializes in the discovery and design of novel nucleoside or nucleotide based enzyme inhibitors that may be used to treat infections or cancer. She has authored over 90 peer-reviewed publications, is an inventor of five issued US patents, and is a professor in the department of chemistry and biochemistry at the University of Maryland, Baltimore County. Her international impact includes scientific collaborations, policy advising and diplomatic appointments in biosecurity efforts.

References

  1. ↑ Neidle, S.; Rogers, D.; Hursthouse, M. B. (1978). "The crystal and molecular structure of streptomycin oxime selenate tetrahydrate". Proceedings of the Royal Society of London. A. Mathematical and Physical Sciences. 359 (1698): 365–388. Bibcode:1978RSPSA.359..365N. doi:10.1098/rspa.1978.0047. S2CID   96093485.
  2. 1 2 3 4 "Iris View Profile". iris.ucl.ac.uk. Retrieved 2023-02-14.
  3. ↑ Parkinson, Gary N.; Lee, Michael P. H.; Neidle, Stephen (2002). "Crystal structure of parallel quadruplexes from human telomeric DNA". Nature. 417 (6891): 876–880. Bibcode:2002Natur.417..876P. doi:10.1038/nature755. PMID   12050675. S2CID   4422211.
  4. ↑ "Prof Stephen Neidle: Emeritus Professor of Chemical Biology and CRUK Professorial Fellow". ucl.ac.uk. 25 April 2018. Retrieved 2023-02-15.
  5. ↑ "Major Advance Which Will Affect Future Of Cancer Drug Development". www.icr.ac.uk. Retrieved 2023-02-14.
  6. ↑ "A new way to treat prostate cancer: The story of abiraterone". The Institute of Cancer Research. 2012-09-10. Archived from the original on 9 July 2012. Retrieved 2023-02-15.
  7. ↑ Mann J, Taylor PW, Dorgan CR, Johnson PD, Wilson FX, Vickers R, Dale AJ, Neidle S (2015). "Researchers develop entirely new antibiotic to treat gut infection". MedChemComm. 6 (8): 1420–26. doi:10.1039/c5md00238a. PMC   4756575 . PMID   26949507.
  8. ↑ UCL (2022-04-12). "Researchers develop entirely new antibiotic to treat gut infections". Research Impact. Retrieved 2023-02-14.
  9. ↑ Sun, Daekyu; Thompson, Brian; Cathers, Brian E.; Salazar, Miguel; Kerwin, Sean M.; Trent, John O.; Jenkins, Terence C.; Neidle, Stephen; Hurley, Laurence H. (1997). "Inhibition of Human Telomerase by a G-Quadruplex-Interactive Compound". Journal of Medicinal Chemistry. 40 (14): 2113–2116. doi:10.1021/jm970199z. PMID   9216827.
  10. ↑ Read, Martin; Harrison, R. John; Romagnoli, Barbara; Tanious, Farial A.; Gowan, Sharon H.; Reszka, Anthony P.; Wilson, W. David; Kelland, Lloyd R.; Neidle, Stephen (2001). "Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors". Proceedings of the National Academy of Sciences. 98 (9): 4844–4849. Bibcode:2001PNAS...98.4844R. doi: 10.1073/pnas.081560598 . PMC   33125 . PMID   11309493.
  11. ↑ Balasubramanian, Shankar; Hurley, Laurence H.; Neidle, Stephen (2011). "Targeting G-quadruplexes in gene promoters: A novel anticancer strategy?". Nature Reviews Drug Discovery. 10 (4): 261–275. doi:10.1038/nrd3428. PMC   3119469 . PMID   21455236.
  12. ↑ Neidle, Stephen (2016). "Quadruplex Nucleic Acids as Novel Therapeutic Targets". Journal of Medicinal Chemistry. 59 (13): 5987–6011. doi:10.1021/acs.jmedchem.5b01835. PMID   26840940.
  13. ↑ Neidle, Stephen (2017). "Quadruplex nucleic acids as targets for anticancer therapeutics". Nature Reviews Chemistry. 1 (5). doi:10.1038/s41570-017-0041.
  14. ↑ Marchetti, Chiara; Zyner, Katherine G.; Ohnmacht, Stephan A.; Robson, Mathew; Haider, Shozeb M.; Morton, Jennifer P.; Marsico, Giovanni; Vo, Tam; Laughlin-Toth, Sarah; Ahmed, Ahmed A.; Di Vita, Gloria; Pazitna, Ingrida; Gunaratnam, Mekala; Besser, Rachael J.; Andrade, Ana C. G.; Diocou, Seckou; Pike, Jeremy A.; Tannahill, David; Pedley, R. Barbara; Evans, T. R. Jeffry; Wilson, W. David; Balasubramanian, Shankar; Neidle, Stephen (2018). "Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule". Journal of Medicinal Chemistry. 61 (6): 2500–2517. doi:10.1021/acs.jmedchem.7b01781. PMC   5867665 . PMID   29356532.
  15. ↑ Ahmed, Ahmed A.; Angell, Richard; Oxenford, Sally; Worthington, Jenny; Williams, Nicole; Barton, Naomi; Fowler, Thomas G.; o'Flynn, Daniel E.; Sunose, Mihiro; McConville, Matthew; Vo, Tam; Wilson, W. David; Karim, Saadia A.; Morton, Jennifer P.; Neidle, Stephen (2020). "Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models". ACS Medicinal Chemistry Letters. 11 (8): 1634–1644. doi:10.1021/acsmedchemlett.0c00317. PMC   7429975 . PMID   32832034.
  16. ↑ "Qualigen Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for QN-302, a G-Quadruplex (G4)" . Retrieved 2023-02-14.
  17. ↑ "Stephen Neidle". Google Scholar. Retrieved 2023-02-15.
  18. ↑ Neidle, Stephen (2019). "Bioorganic & Medicinal Chemistry Letters – Editorial Board". Archived from the original on 2019-12-12. Retrieved 2023-02-12.
  19. ↑ Rudd, Matt (2 January 2024). "'I love tax': the retired lawyer who brought down Nadhim Zahawi" . Retrieved 2 January 2024.
  20. ↑ "Prof Stephen Neidle: Achievements". iris.ucl.ac.uk. Retrieved 2023-02-14.
  21. ↑ "Bioorganic & Medicinal Chemistry Letters | Stephen Neidle Honour Issue | ScienceDirect.com by Elsevier". www.sciencedirect.com. Retrieved 2023-02-14.
  22. ↑ "George and Christine Sosnovsky Award in Cancer Therapy Winners". rsc.org. Retrieved 2023-02-12.
  23. ↑ "Interdisciplinary Prizes: Previous Winners". rsc.org. Retrieved 2023-02-12.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.