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Derek R. Duckett, PhD

Academic Rank: Senior Member

Overview

Dr. Duckett has a wealth of experience in identifying tractable anti-cancer targets, developing selective small molecule probes of these targets, and in optimizing these leads to generate safety assessment candidates for testing in preclinical tumor models and, ultimately in moving these agents forward into the clinic. Derek is PI of 4 R01 grants and has several ongoing kinase inhibitor programs that are targeting: (i) CK1δ and CK1ε that regulate WNT-β-catenin signaling and DNA repair pathways in metastatic triple negative breast cancer and glioblastoma, respectively; (ii) the transcriptional cyclin-dependent kinases CDK12 and CDK13 in trastuzumab-resistant HER2+ breast cancer; (iii) the ULK1 autophagy kinase in non-small cell lung cancer; and (iv) the ASK1 apoptosis kinase. Finally, Dr. Duckett also has robust research programs evaluating the roles of β-arrestin1 in GPCR-directed stress signaling and genome maintenance.


Discipline

    • Neuro-Oncology
    • Drug Discovery
    • Breast Oncology
    • Chemical Biology and Molecular Medicine Program
    • Melanoma Research Center of Excellence
    • Lung Cancer Center of Excellence

Education & Training

Fellowship:

  • Dundee University, PhD - Biochemistry
Research

    Dr. Duckett earned his PhD degree in Biochemistry from the University of Dundee under the mentorship of Professor David M. J. Lilley, a Member of Royal Society and the Director of the Cancer Research UK Nucleic Acid Structure Research Group, where Derek had a remarkable string of studies that defined the structures for DNA and RNA four-way helical junctions, and how these interact with resolving enzymes (Duckett, et al., Cell, 1988, 1995). Derek then was a Howard Hughes Research Fellow in the laboratory of Nobel Laureate Dr. Paul Modrich, where his work established that mismatch repair was the principal repair pathway invoked by DNA damage induced by cytotoxic chemotherapies, including cisplatin and methylating agents (Duckett et al., PNAS, 1996, 1999). Following his fellowship, Dr. Duckett was a Senior Research Scientist at DuPont Pharmaceuticals and then served as a Research Investigator for GlaxoSmithKline from 2000 to 2005, where he directed several clinical kinase inhibitor campaigns, including two that entered Phase I trials. In 2005, Derek joined the Scripps Research Institute (Scripps) as the Associate Director of the Translational Research Institute, where he directed the biology efforts of the High Throughput Screening Facility. In 2009, Dr. Duckett was appointed as an Assistant Professor in the Department of Molecular Therapeutics at Scripps and he was promoted to Associate Professor in 2013.            

Publications

  • Quereda V, Hou S, Madoux F, Scampavia L, Spicer TP, Duckett D. A Cytotoxic Three-Dimensional-Spheroid, High-Throughput Assay Using Patient-Derived Glioma Stem Cells. SLAS Discov. 2018 Sep;23(8):842-849. Pubmedid: 29750582. Pmcid: PMC6102052.
  • Monastyrskyi A, Nilchan N, Quereda V, Noguchi Y, Ruiz C, Grant W, Cameron M, Duckett D, Roush W. Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer. Bioorg Med Chem. 2018 Feb;26(3):590-602. Pubmedid: 29289448. Pmcid: PMC5803353.
  • Monastyrskyi A, Bayle S, Quereda V, Grant W, Cameron M, Duckett D, Roush W. Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors. Bioorg Med Chem Lett. 2018 Feb;28(3):400-404. Pubmedid: 29277458. Pmcid: PMC5999544.
  • Wood SD, Grant W, Adrados I, Choi JY, Alburger JM, Duckett DR, Roush WR. HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors. ACS Med Chem Lett. 2017 Dec;8(12):1258-1263. Pubmedid: 29259744. Pmcid: PMC5733266.
  • Velagapudi SP, Cameron MD, Haga CL, Rosenberg LH, Lafitte M, Duckett DR, Phinney DG, Disney MD. Design of a small molecule against an oncogenic noncoding RNA. Proc Natl Acad Sci U S A. 2016 May;113(21):5898-5903. Pubmedid: 27170187. Pmcid: PMC4889373.
  • Rosenberg LH, Cleveland JL, Roush WR, Duckett DR. CK1δ: an exploitable vulnerability in breast cancer. Ann Transl Med. 2016 Dec;4(23):474. Pubmedid: 28090530. Pmcid: PMC5220019.
  • Corzo CA, Mari Y, Chang MR, Khan T, Kuruvilla D, Nuhant P, Kumar N, West GM, Duckett DR, Roush WR, Griffin PR. Antiproliferation activity of a small molecule repressor of liver receptor homolog 1. Mol Pharmacol. 2015 Feb;87(2):296-304. Pubmedid: 25473120. Pmcid: PMC4293447.
  • Rosenberg LH, Lafitte M, Quereda V, Grant W, Chen W, Bibian M, Noguchi Y, Fallahi M, Yang C, Chang JC, Roush WR, Cleveland JL, Duckett DR. Therapeutic targeting of casein kinase 1δ in breast cancer. Sci Transl Med. 2015 Dec;7(318):318ra202. Pubmedid: 26676609. Pmcid: PMC4809734.
  • Saunders VC, Lafitte M, Adrados I, Quereda V, Feurstein D, Ling Y, Fallahi M, Rosenberg LH, Duckett DR. Identification of an EGFRvIII-JNK2-HGF/c-Met-Signaling Axis Required for Intercellular Crosstalk and Glioblastoma Multiforme Cell Invasion. Mol Pharmacol. 2015 Dec;88(6):962-969. Pubmedid: 26452771.
  • Rosenberg LH, Lafitte M, Grant W, Chen W, Cleveland JL, Duckett DR. Development of an HTS-Compatible Assay for the Discovery of Ulk1 Inhibitors. J Biomol Screen. 2015 Aug;20(7):913-920. Pubmedid: 25851035. Pmcid: PMC4744088.
  • Sturchler E, Chen W, Spicer T, Hodder P, McDonald P, Duckett D. Development of an HTS-compatible assay for the discovery of ASK1 signalosome inhibitors using alphascreen technology. Assay Drug Dev Technol. 2014 May;12(4):229-237. Pubmedid: 24831789. Pmcid: PMC4025566.
  • He Y, Duckett D, Chen W, Ling YY, Cameron MD, Lin L, Ruiz CH, Lograsso PV, Kamenecka TM, Koenig M. Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett. 2014 Jan;24(1):161-164. Pubmedid: 24332487. Pmcid: PMC4540177.
  • Jiang R, Frackowiak B, Shin Y, Song X, Chen W, Lin L, Cameron MD, Duckett DR, Kamenecka TM. Design and synthesis of 1-aryl-5-anilinoindazoles as c-Jun N-terminal kinase inhibitors. Bioorg Med Chem Lett. 2013 May;23(9):2683-2687. Pubmedid: 23518277.
  • Sturchler E, Feurstein D, Chen W, McDonald P, Duckett D. Stress-induced nuclear import of apoptosis signal-regulating kinase 1 is mediated by karyopherin α2/β1 heterodimer. Biochim Biophys Acta. 2013 Mar;1833(3):583-592. Pubmedid: 23123190.
  • Bibian M, Rahaim RJ, Choi JY, Noguchi Y, Schürer S, Chen W, Nakanishi S, Licht K, Rosenberg LH, Li L, Feng Y, Cameron MD, Duckett DR, Cleveland JL, Roush WR. Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. Bioorg Med Chem Lett. 2013 Aug;23(15):4374-4380. Pubmedid: 23787102. Pmcid: PMC3783656.
  • Noël R, Shin Y, Song X, He Y, Koenig M, Chen W, Ling YY, Lin L, Ruiz CH, LoGrasso P, Cameron MD, Duckett DR, Kamenecka TM. Synthesis and SAR of 4-(pyrazol-3-yl)-pyridines as novel c-jun N-terminal kinase inhibitors. Bioorg Med Chem Lett. 2011 May;21(9):2732-2735. Pubmedid: 21185177. Pmcid: PMC3081976.
  • He Y, Kamenecka TM, Shin Y, Song X, Jiang R, Noel R, Duckett D, Chen W, Ling YY, Cameron MD, Lin L, Khan S, Koenig M, LoGrasso PV. Synthesis and SAR of novel quinazolines as potent and brain-penetrant c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett. 2011 Mar;21(6):1719-1723. Pubmedid: 21316221. Pmcid: PMC3052630.
  • Kumar N, Kojetin DJ, Solt LA, Kumar KG, Nuhant P, Duckett DR, Cameron MD, Butler AA, Roush WR, Griffin PR, Burris TP. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. Acs Chem Biol. 2011 Mar;6(3):218-222. Pubmedid: 21090593. Pmcid: PMC3076127.
  • Hahmann C, Weiser A, Duckett D, Schroeter T. A predictive nuclear translocation assay for spliced x-box-binding protein 1 identifies compounds with known organ toxicities. Assay Drug Dev Technol. 2011 Feb;9(1):79-87. Pubmedid: 20858054.
  • Song X, Chen W, Lin L, Ruiz CH, Cameron MD, Duckett DR, Kamenecka TM. Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors. Bioorg Med Chem Lett. 2011 Dec;21(23):7072-7075. Pubmedid: 22004719.
  • Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, Towers AJ, Williams B, Lam CM, Xiao K, Shenoy SK, Gregory SG, Ahn S, Duckett DR, Lefkowitz RJ. A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature. 2011 Aug;477(7364):349-353. Pubmedid: 21857681. Pmcid: PMC3628753.
  • Chambers JW, Pachori A, Howard S, Ganno M, Hansen D, Kamenecka T, Song X, Duckett D, Chen W, Ling YY, Cherry L, Cameron MD, Lin L, Ruiz CH, Lograsso P. Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease. ACS Chem Neurosci. 2011 Apr;2(4):198-206. Pubmedid: 21666839. Pmcid: PMC3110074.
  • Duckett DR, Cameron MD. Metabolism considerations for kinase inhibitors in cancer treatment. Expert Opin Drug Metab Toxicol. 2010 Oct;6(10):1175-1193. Pubmedid: 20684746. Pmcid: PMC2940961.
  • Sturchler E, Feurstein D, McDonald P, Duckett D. Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry-Us. 2010 May;49(19):4094-4102. Pubmedid: 20364819.
  • Kamenecka T, Jiang R, Song X, Duckett D, Chen W, Ling YY, Habel J, Laughlin JD, Chambers J, Figuera-Losada M, Cameron MD, Lin L, Ruiz CH, LoGrasso PV. Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine c-jun-N-terminal kinase (JNK) inhibitors. J Med Chem. 2010 Jan;53(1):419-431. Pubmedid: 19947601. Pmcid: PMC2804074.
  • Kamenecka T, Habel J, Duckett D, Chen W, Ling YY, Frackowiak B, Jiang R, Shin Y, Song X, LoGrasso P. Structure-activity relationships and X-ray structures describing the selectivity of aminopyrazole inhibitors for c-Jun N-terminal kinase 3 (JNK3) over p38. J Biol Chem. 2009 May;284(19):12853-12861. Pubmedid: 19261605. Pmcid: PMC2676016.
  • Shin Y, Chen W, Habel J, Duckett D, Ling YY, Koenig M, He Y, Vojkovsky T, LoGrasso P, Kamenecka TM. Synthesis and SAR of piperazine amides as novel c-jun N-terminal kinase (JNK) inhibitors. Bioorg Med Chem Lett. 2009 Jun;19(12):3344-3347. Pubmedid: 19433357. Pmcid: PMC2737472.
  • Yin Y, Lin L, Ruiz C, Cameron MD, Pocas J, Grant W, Schröter T, Chen W, Duckett D, Schürer S, Lograsso P, Feng Y. Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors. Bioorg Med Chem Lett. 2009 Dec;19(23):6686-6690. Pubmedid: 19837589.
  • Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, Lafrance LV, Li M, Safonov IG, Takata DT, Venslavsky JW, Yamashita DS, Choudhry AE, Copeland RA, Lai Z, Schaber MD, Tummino PJ, Strum SL, Wood ER, Duckett DR, Eberwein D, Knick VB, Lansing TJ, McConnell RT, Zhang S, Minthorn EA, Concha NO, Warren GL, Kumar R. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J Med Chem. 2008 Sep;51(18):5663-5679. Pubmedid: 18800763.
  • Chen YT, Bannister TD, Weiser A, Griffin E, Lin L, Ruiz C, Cameron MD, Schürer S, Duckett D, Schröter T, LoGrasso P, Feng Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorg Med Chem Lett. 2008 Dec;18(24):6406-6409. Pubmedid: 18990570.
  • Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K, Kahana JA, Geske RS, Kleymenova EV, Choudhry AE, Lai Z, Leber JD, Minthorn EA, Strum SL, Wood ER, Huang PS, Copeland RA, Kumar R. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008 Apr;68(7):2366-2374. Pubmedid: 18381444.
  • Jiang R, Duckett D, Chen W, Habel J, Ling YY, LoGrasso P, Kamenecka TM. 3,5-Disubstituted quinolines as novel c-Jun N-terminal kinase inhibitors. Bioorg Med Chem Lett. 2007 Nov;17(22):6378-6382. Pubmedid: 17911023.
  • Rech JC, Yato M, Duckett D, Ember B, LoGrasso PV, Bergman RG, Ellman JA. Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation. J Am Chem Soc. 2007 Jan;129(3):490-491. Pubmedid: 17227002. Pmcid: PMC2556147.
  • Lansing TJ, McConnell RT, Duckett DR, Spehar GM, Knick VB, Hassler DF, Noro N, Furuta M, Emmitte KA, Gilmer TM, Mook RA, Cheung M. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol Cancer Ther. 2007 Feb;6(2):450-459. Pubmedid: 17267659.
  • Duckett DR, Bronstein SM, Taya Y, Modrich P. hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage. Proc Natl Acad Sci U S A. 1999 Oct;96(22):12384-12388. Pubmedid: 10535931. Pmcid: PMC22926.
  • Walter F, Murchie AI, Duckett DR, Lilley DM. Global structure of four-way RNA junctions studied using fluorescence resonance energy transfer. RNA. 1998 Jun;4(6):719-728. Pubmedid: 9622130. Pmcid: PMC1369653.
  • Duckett DR, Murchie AI, Clegg RM, Bassi GS, Giraud-Panis MJ, Lilley DM. Nucleic acid structure and recognition. Biophys Chem. 1997 Oct;68(1-3):53-62. Pubmedid: 17029905.
  • Mu D, Tursun M, Duckett DR, Drummond JT, Modrich P, Sancar A. Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems. Mol Cell Biol. 1997 Feb;17(2):760-769. Pubmedid: 9001230. Pmcid: PMC231802.
  • Duckett DR, Drummond JT, Murchie AI, Reardon JT, Sancar A, Lilley DM, Modrich P. Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci U S A. 1996 Jun;93(13):6443-6447. Pubmedid: 8692834. Pmcid: PMC39042.
  • Giraud-Panis MJ, Duckett DR, Lilley DM. The modular character of a DNA junction-resolving enzyme: a zinc-binding motif in bacteriophage T4 endonuclease VII. J Mol Biol. 1995 Oct;252(5):596-610. Pubmedid: 7563077.
  • Duckett DR, Murchie AI, Giraud-Panis MJ, Pöhler JR, Lilley DM. Structure of the four-way DNA junction and its interaction with proteins. Philos Trans R Soc Lond B Biol Sci. 1995 Jan;347(1319):27-36. Pubmedid: 7746850.
  • Duckett DR, Panis MJ, Lilley DM. Binding of the junction-resolving enzyme bacteriophage T7 endonuclease I to DNA: separation of binding and catalysis by mutation. J Mol Biol. 1995 Feb;246(1):95-107. Pubmedid: 7853409.
  • Duckett DR, Murchie AI, Lilley DM. The global folding of four-way helical junctions in RNA, including that in U1 snRNA. Cell. 1995 Dec;83(6):1027-1036. Pubmedid: 8521503.
  • Pöhler JR, Duckett DR, Lilley DM. Structure of four-way DNA junctions containing a nick in one strand. J Mol Biol. 1994 Apr;238(1):62-74. Pubmedid: 8145257.
  • Welch JB, Duckett DR, Lilley DM. Structures of bulged three-way DNA junctions. Nucleic Acids Res. 1993 Sep;21(19):4548-4555. Pubmedid: 8233789. Pmcid: PMC311188.
  • Duckett DR, Murchie AI, Bhattacharyya A, Clegg RM, Diekmann S, von Kitzing E, Lilley DM. The structure of DNA junctions and their interaction with enzymes. Eur J Biochem. 1993 Jan;211(1-2):285-295. Pubmedid: 8425539.
  • Lilley DM, Bhattacharyya A, McAteer SP, Duckett DR. Gel electrophoretic analysis of the structure of nucleic acids. Biochem Soc T. 1993 Feb;21(1):111-116. Pubmedid: 7680620.
  • Duckett DR, Lilley DM. Effects of base mismatches on the structure of the four-way DNA junction. J Mol Biol. 1991 Sep;221(1):147-161. Pubmedid: 1920402.
  • Duckett DR, Lilley DM. The three-way DNA junction is a Y-shaped molecule in which there is no helix-helix stacking. Embo J. 1990 May;9(5):1659-1664. Pubmedid: 2328731. Pmcid: PMC551862.
  • Duckett DR, Murchie AI, Lilley DM. The role of metal ions in the conformation of the four-way DNA junction. Embo J. 1990 Feb;9(2):583-590. Pubmedid: 2303044. Pmcid: PMC551705.
  • Murchie AI, Clegg RM, von Kitzing E, Duckett DR, Diekmann S, Lilley DM. Fluorescence energy transfer shows that the four-way DNA junction is a right-handed cross of antiparallel molecules. Nature. 1989 Oct;341(6244):763-766. Pubmedid: 2797209.
  • Duckett DR, Murchie AI, Diekmann S, von Kitzing E, Kemper B, Lilley DM. The structure of the Holliday junction, and its resolution. Cell. 1988 Oct;55(1):79-89. Pubmedid: 3167979.