Smaill, Jeff - The University of Auckland - Faculty of Medical and Health Sciences

个人简介

I obtained my BSc (Hons) and PhD degrees in the field of synthetic organic chemistry from the University of Otago in the laboratory of Professor Peter K Grant. I then completed a postdoctoral fellowship at the University of Cambridge under the supervision of Professor Ian Paterson, developing a biomimetic approach to the total synthesis of the polyether antibiotic Etheromycin. I am currently a Associate Professor at the Auckland Cancer Society Research Centre in the Faculty of Medical and Health Sciences at the University of Auckland. I have been the Principal Investigator of several large public good health research grants including prestigious grants from the Health Research Council of New Zealand, the US National Institutes of Health and the European Research Council. I am also a Associate Investigator of the Maurice Wilkins Centre for Molecular Biodiscovery, one of New Zealand’s ten Centres of Research Excellence. I have had 27 years of experience leading drug discovery programmes in collaboration with University start-up companies, small to medium sized biotechnology companies and large pharmaceutical companies. I have acted as a paid scientific consultant for Proacta Incorporated, Threshold Pharmaceuticals, Convert Pharmaceuticals, Rain Therapeutics and Kezar Life Sciences. I have served as a member of the Scientific Advisory Board of Rain Therapeutics. In 2018, I won the Vice Chancellor’s Commercialisation Medal, the University of Auckland’s highest research award. I have extensive experience in the design and synthesis of ATP-competitive small molecule kinase inhibitors. I have been involved in the elucidation of structure-activity relationships for 4-anilinoquinazolines and 4-anilinopyridopyrimidines as irreversible inhibitors of the Human Epidermal Growth Factor Receptor (HER) family. My research in collaboration with Pfizer Global Research and Development has included the discovery of canertinib, the first irreversible kinase inhibitor to enter clinical trial. Further collaboration with Pfizer lead to the discovery of dacomitinib, a leading second generation irreversible EGFR/HER2 inhibitor that successfully completed phase III trial and gained global approval in 2018 for the treatment of lung cancer. I have published on structure-based design of inhibitors targeted at EGFR, HER2, FGFR, PDGFR, WEE1, CHK1, SRC and RAF. Most recently I have been focused on drug design strategies that impart improved selectivity to cancer treatment, including the discovery and development of novel hypoxia-activated prodrugs. I am a co-inventor of the clinical stage prodrug tarloxotinib bromide, a first-in-class hypoxia-activated irreversible EGFR/HER2 inhibitor under license to Rain Therapeutics. I am also a co-inventor of CP-506, a hypoxia-activated prodrug recently selected for clinical trial in Europe by Convert Pharmaceuticals and LX-132, an irreversible pan-FGFR inhibitor that has been selected for clinical trial in China by Lixin Pharmaceuticals. I have published 72 peer-reviewed papers and 3 book chapters, while being listed as an inventor on 18 international PCT applications and 22 granted patents.

研究领域

Medicinal chemistry Drug design and development Molecular therapeutics Cancer research Organic synthesis Hypoxia Gene therapy Fluorogenic probes Kinase inhibitors Bioreductive prodrugs Oncolytic viruses Bacterial nitroreductases Hypoxia-activated prodrugs

近期论文

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Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells. 29 Sep 2022Journal of medicinal chemistry. Xu F, Zhang X, Chen Z, He S, Guo J, Yu L, Wang Y, Hou C, Ai-Furas H, Zheng Z, Smaill JB, Patterson AV, Zhang Z-M, Chen L, Ren X, Ding K. 10.1021/ACS.JMEDCHEM.2C01246 Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411^NTR leading to therapeutic benefit. Jul 2022Cancer gene therapy29(7):1021-1032. Singleton DC, Mowday AM, Guise CP, Syddall SP, Bai SY, Li D, Ashoorzadeh A, Smaill JB, Wilson WR, Patterson AV. 10.1038/S41417-021-00409-2 Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.10 Mar 2022Journal of medicinal chemistry65(6):5113-5133. Shao M, Chen X, Yang F, Song X, Zhou Y, Lin Q, Fu Y, Ortega R, Lin X, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X. 10.1021/ACS.JMEDCHEM.2C00096 Interrogation of the Structure-Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications. Feb 2022Pharmaceuticals (Basel, Switzerland)15(2):185. Ashoorzadeh A, Mowday AM, Guise CP, Silva S, Bull MR, Abbattista MR, Copp JN, Williams EM, Ackerley DF, Patterson AV, Smaill JB. 10.3390/PH15020185 Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours. Feb 2022 Cancer gene therapy29(2):178-188. Mowday AM, Dubois LJ, Kubiak AM, Chan-Hyams JVE, Guise CP, Ashoorzadeh A, Lambin P, Ackerley DF, Smaill JB, Minton NP, Theys J, Patterson AV. 10.1038/S41417-021-00296-7 Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors. Jan 2022Journal of medicinal chemistry65(1):58-83. Lu X, Smaill JB, Patterson AV, Ding K. 10.1021/ACS.JMEDCHEM.1C01719 Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling. Jan 2022Frontiers in pharmacology13:803602. Jackson-Patel V, Liu E, Bull MR, Ashoorzadeh A, Bogle G, Wolfram A, Hicks KO, Smaill JB, Patterson AV. 10.3389/FPHAR.2022.803602 Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506. Dec 2021Molecular cancer therapeutics20(12):2372-2383. van der Wiel AMA, Jackson-Patel V, Niemans R, Yaromina A, Liu E, Marcus D, Mowday AM, Lieuwes NG, Biemans R, Lin X, Fu Z, Kumara S, Jochems A, Ashoorzadeh A, Anderson RF, Hicks KO, Bull MR, Abbattista MR, Guise CP, Deschoemaeker S, Thiolloy S, Heyerick A, Solivio MJ, Balbo S, Smaill JB, Theys J, Dubois LJ, Patterson AV, Lambin P. 10.1158/1535-7163.MCT-21-0406 Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3. 26 Nov 2021Pharmaceuticals (Basel, Switzerland)14(12):1231. Abbattista MR, Ashoorzadeh A, Guise CP, Mowday AM, Mittra R, Silva S, Hicks KO, Bull MR, Jackson-Patel V, Lin X, Prosser GA, Lambie NK, Dachs GU, Ackerley DF, Smaill JB, Patterson AV. 10.3390/PH14121231 TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery. Oct 2021Drug discovery today26(10):2445-2455. Xiang S, Song S, Tang H, Smaill JB, Wang A, Xie H, Lu X. 10.1016/J.DRUDIS.2021.05.016 Fourth-Generation Analogues of the Anticancer Peptaibol Culicinin D: Probing the Effects of Hydrophobicity and Halogenation on Cytotoxicity. 10 Jun 2021Synthesis53(22):4239-4245Thieme. Kasim JK, Kavianinia I, Bull M, Harris PWR, Smaill JB, Patterson AV, Brimble MA. 10.1055/S-0040-1706264 Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents. Jun 2021Molecules (Basel, Switzerland)26(11):3327. Omran Z, Guise CP, Chen L, Rauch C, Abdalla AN, Abdullah O, Sindi IA, Fischer PM, Smaill JB, Patterson AV, Liu Y, Wang Q. 10.3390/MOLECULES26113327 Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy. 24 Apr 2021Cells10(5):1006. Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. 10.3390/CELLS10051006 Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506. 19 Apr 2021Research SquareResearch Square Platform LLC. Wiel AMAVD, Jackson-Patel V, Niemans R, Yaromina A, Liu E, Marcus D, Mowday A, Lieuwes N, Biemans R, Lin X, Fu Z, Kumara S, Jochems A, Ashoorzadeh A, Anderson R, Hicks K, Bull M, Abbattista M, Guise C, Deschoemaeker S, Thiolloy S, Heyerick A, Solivio M, Balbo S, Smaill J, Theys J, Dubois L, Patterson A, Lambin P. 10.21203/RS.3.RS-438613/V1 Investigation of Covalent Warheads in the Design of 2-Aminopyrimidine-based FGFR4 Inhibitors. Apr 2021ACS medicinal chemistry letters12(4):647-652. Deng W, Chen X, Jiang K, Song X, Huang M, Tu Z-C, Zhang Z, Lin X, Ortega R, Patterson AV, Smaill JB, Ding K, Chen S, Chen Y, Lu X. 10.1021/ACSMEDCHEMLETT.1C00052 Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes. Mar 2021Clinical cancer research : an official journal of the American Association for Cancer Research27(5):1463-1475. Estrada-Bernal A, Le AT, Doak AE, Tirunagaru VG, Silva S, Bull MR, Smaill JB, Patterson AV, Kim C, Liu SV, Doebele RC. 10.1158/1078-0432.CCR-20-3555 Chemical Probes for Kinases. DISCOVERY AND UTILITY OF CHEMICAL PROBES IN TARGET DISCOVERYDISCOVERY AND UTILITY OF CHEMICAL PROBES IN TARGET DISCOVERY16:182-213 (32 pages)ROYAL SOC CHEMISTRY. Lu X, Smaill JB, Ding K, Brennan P (Editor), Rodriguez SV (Editor) Directed evolution of the B. subtilis nitroreductase YfkO improves activation of the PET-capable probe SN33623 and CB1954 prodrug. Jan 2021Biotechnology letters43(1):203-211. Rich MH, Sharrock AV, Ashoorzadeh A, Patterson AV, Smaill JB, Ackerley DF. 10.1007/S10529-020-02992-0 Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. Dec 2020Journal of medicinal chemistry63(23):14404-14424. Chen H, Smaill JB, Liu T, Ding K, Lu X. 10.1021/ACS.JMEDCHEM.0C01312 OC-0203: Eliminating tumour hypoxia to improve the impact of immunotherapy. 1 Nov 2020Radiotherapy and Oncology152:s102Elsevier. Marcus D, Van der Wiel A, Biemans R, Lieuwes N, Heyerick A, Smaill J, Patterson A, Theys J, Yaromina A, Lambin P, Dubois L. 10.1016/S0167-8140(21)00227-9