Imperial College London

Dr Matthew J. Fuchter

Faculty of Natural SciencesDepartment of Chemistry

Reader in Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 5815m.fuchter

 
 
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Location

 

739ChemistrySouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

100 results found

Ali S, Patel H, Periyasamy M, Sava G, Bondke A, Slafer BW, Kroll SHB, Barbazanges MV, Starkey RG, Ottaviani S, Harrod AE, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes Cet al., 2018, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment, Molecular Cancer Therapeutics, ISSN: 1535-7163

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC50 of 40nM; IC50 values for CDK1, CDK2, CDK5 and CDK9 were 45-, 15-, 230- and 30-fold higher. In vitro studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI50 values ranging between 0.2-0.3 µM. In xenografts of both breast and colorectal cancers, the drug has substantial anti-tumor effects. Additionally, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia, and small-cell lung cancer.

JOURNAL ARTICLE

Fuchter MJ, 2018, Editorial, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 26, Pages: 2919-2920, ISSN: 0968-0896

JOURNAL ARTICLE

Hazel P, Kroll SHB, Bondke A, Barbazanges M, Patel H, Fuchter MJ, Coombes RC, Ali S, Barrett AGM, Freemont PSet al., 2018, Inhibitor Selectivity for Cyclin-Dependent Kinase7: A Structural, Thermodynamic, and Modelling Study (vol 12, pg 372, 2017), CHEMMEDCHEM, Vol: 13, Pages: 207-207, ISSN: 1860-7179

JOURNAL ARTICLE

Lubin AS, Rueda-Zubiaurre A, Matthews H, Baumann H, Fisher FR, Morales-Sanfrutos J, Hadayizadeh KS, Nardella F, Tate EW, Baum J, Scherf A, Fuchter MJet al., 2018, Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in Plasmodium falciparum, ACS INFECTIOUS DISEASES, Vol: 4, Pages: 523-530, ISSN: 2373-8227

JOURNAL ARTICLE

Montgomery KS, Davidson RWM, Cao B, Williams B, Simpson GW, Nilsson SK, Chiefari J, Fuchter MJet al., 2018, Effective macrophage delivery using RAFT copolymer derived nanoparticles, POLYMER CHEMISTRY, Vol: 9, Pages: 131-137, ISSN: 1759-9954

JOURNAL ARTICLE

Patel H, Periyasamy M, Sava GP, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC, Ali Set al., 2018, ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment, UK Breast Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 1156-1166, ISSN: 1535-7163

CONFERENCE PAPER

Rice B, LeBlanc LM, Otero-de-la-Roza A, Fuchter MJ, Johnson ER, Nelson J, Jelfs KEet al., 2018, A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6] helicene molecule, NANOSCALE, Vol: 10, Pages: 1865-1876, ISSN: 2040-3364

JOURNAL ARTICLE

Rice B, LeBlanc LM, Otero-de-la-Roza A, Fuchter MJ, Johnson ER, Nelson J, Jelfs KEet al., 2018, Correction: A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule., Nanoscale, Vol: 10

Correction for 'A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule' by Beth Rice et al., Nanoscale, 2018, 10, 1865-1876.

JOURNAL ARTICLE

Sapsford JS, Scott DJ, Allcock NJ, Fuchter MJ, Tighe CJ, Ashley AEet al., 2018, Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid, ADVANCED SYNTHESIS & CATALYSIS, Vol: 360, Pages: 1066-1071, ISSN: 1615-4150

JOURNAL ARTICLE

Yang Y, Rice B, Shi X, Brandt JR, Correa da Costa R, Hedley GJ, Smilgies D-M, Frost JM, Samuel IDW, Otero-de-la-Roza A, Johnson ER, Jelfs KE, Nelson J, Campbell AJ, Fuchter MJet al., 2018, Correction to Emergent Properties of an Organic Semiconductor Driven by its Molecular Chirality., ACS Nano

JOURNAL ARTICLE

Brandt JR, Pospisil L, Bednarova L, da Costa RC, White AJP, Mori T, Teply F, Fuchter MJet al., 2017, Intense redox-driven chiroptical switching with a 580 mV hysteresis actuated through reversible dimerization of an azoniahelicene, CHEMICAL COMMUNICATIONS, Vol: 53, Pages: 9059-9062, ISSN: 1359-7345

JOURNAL ARTICLE

Brandt JR, Salerno F, Fuchter MJ, 2017, The added value of small-molecule chirality in technological applications, NATURE REVIEWS CHEMISTRY, Vol: 1, ISSN: 2397-3358

JOURNAL ARTICLE

Calbo J, Weston CE, White AJP, Rzepa HS, Contreras-Garcia J, Fuchter MJet al., 2017, Tuning Azoheteroarene Photoswitch Performance through Heteroaryl Design, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 139, Pages: 1261-1274, ISSN: 0002-7863

JOURNAL ARTICLE

Hazel P, Kroll SHB, Bondke A, Barbazanges M, Patel H, Fuchter MJ, Coombes RC, Ali S, Barrett AGM, Freemont PSet al., 2017, Inhibitor Selectivity for Cyclin-Dependent Kinase7: AStructural, Thermodynamic, and Modelling Study, CHEMMEDCHEM, Vol: 12, Pages: 372-380, ISSN: 1860-7179

JOURNAL ARTICLE

Scott DJ, Fuchter MJ, Ashley AE, 2017, Designing effective 'frustrated Lewis pair' hydrogenation catalysts, CHEMICAL SOCIETY REVIEWS, Vol: 46, Pages: 5689-5700, ISSN: 0306-0012

JOURNAL ARTICLE

Sundriyal S, Chen PB, Lubin AS, Lueg GA, Li F, White AJP, Malmquist NA, Vedadi M, Scherf A, Fuchter MJet al., 2017, Histone lysine methyltransferase structure activity relationships that allow for segregation of G9a inhibition and anti-Plasmodium activity, MEDCHEMCOMM, Vol: 8, Pages: 1069-1092, ISSN: 2040-2503

JOURNAL ARTICLE

Sundriyal S, Moniot S, Mahmud Z, Yao S, Di Fruscia P, Reynolds CR, Dexter DT, Sternberg MJ, Lam EW, Steegborn C, Fuchter MJet al., 2017, Thienopyrimidinone based sirtuin-2 (SIRT2)-selective inhibitors bind in the ligand induced 'selectivity pocket'., Journal of Medicinal Chemistry, Vol: 60, Pages: 1928-1945, ISSN: 0022-2623

Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a co-crystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported 'selectivity pocket', but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.

JOURNAL ARTICLE

Weston CE, Kraemer A, Colin F, Yildiz O, Baud MGJ, Meyer-Almes F-J, Fuchter MJet al., 2017, Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors, ACS INFECTIOUS DISEASES, Vol: 3, Pages: 152-161, ISSN: 2373-8227

JOURNAL ARTICLE

Yang Y, Rice B, Shi X, Brandt JR, Correa da Costa R, Hedley GJ, Smilgies D-M, Frost JM, Samuel IDW, Otero-de-la-Roza A, Johnson ER, Jelfs KE, Nelson J, Campbell AJ, Fuchter MJet al., 2017, Emergent Properties of an Organic Semiconductor Driven by its Molecular Chirality, ACS Nano, Vol: 11, Pages: 8329-8338, ISSN: 1936-0851

Chiral molecules exist as pairs of nonsuperimposable mirror images; a fundamental symmetry property vastly underexplored in organic electronic devices. Here, we show that organic field-effect transistors (OFETs) made from the helically chiral molecule 1-aza[6]helicene can display up to an 80-fold difference in hole mobility, together with differences in thin-film photophysics and morphology, solely depending on whether a single handedness or a 1:1 mixture of left- and right-handed molecules is employed under analogous fabrication conditions. As the molecular properties of either mirror image isomer are identical, these changes must be a result of the different bulk packing induced by chiral composition. Such underlying structures are investigated using crystal structure prediction, a computational methodology rarely applied to molecular materials, and linked to the difference in charge transport. These results illustrate that chirality may be used as a key tuning parameter in future device applications.

JOURNAL ARTICLE

Brandt JR, Wang X, Yang Y, Campbell AJ, Fuchter MJet al., 2016, Circularly Polarized Phosphorescent Electroluminescence with a High Dissymmetry Factor from PHOLEDs Based on a Platinahelicene, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 138, Pages: 9743-9746, ISSN: 0002-7863

JOURNAL ARTICLE

Chen PB, Ding S, Zanghi G, Soulard V, DiMaggio PA, Fuchter MJ, Mecheri S, Mazier D, Scherf A, Malmquist NAet al., 2016, Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322

JOURNAL ARTICLE

Davidson RWM, Fuchter MJ, 2016, Direct NHC-catalysed redox amidation using CO2 for traceless masking of amine nucleophiles, CHEMICAL COMMUNICATIONS, Vol: 52, Pages: 11638-11641, ISSN: 1359-7345

JOURNAL ARTICLE

Scott DJ, Phillips NA, Sapsford JS, Deacy AC, Fuchter MJ, Ashley AEet al., 2016, Versatile Catalytic Hydrogenation Using A Simple Tin(IV) Lewis Acid, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 55, Pages: 14738-14742, ISSN: 1433-7851

JOURNAL ARTICLE

Weston CE, Richardson RD, Fuchter MJ, 2016, Photoswitchable basicity through the use of azoheteroarenes, CHEMICAL COMMUNICATIONS, Vol: 52, Pages: 4521-4524, ISSN: 1359-7345

JOURNAL ARTICLE

Weston CE, Richardson RD, Haycock PR, White AJP, Fuchter MJet al., 2016, "Arylazopyrazoles: Azoheteroarene Photoswitches Offering Quantitative Isomerization and Long Thermal Half-Lives (vol 136, pg 11878, 2014), JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 138, Pages: 10716-10716, ISSN: 0002-7863

JOURNAL ARTICLE

Anwar A, Archibald S, Audisio D, Badman G, Bergin J, Bew SP, Bloom J, Bushby N, Busigin A, Chan MY, Davies J, Dilworth J, Dunscombe M, Elmore CS, Engstrom P, Fuchter MJ, Geach NJ, Georgin D, Griffiths A, Hansen P, Hardcastle G, Hiatt-Gipson GD, Hickey MJ, Kitson SL, Lashford A, Lenz E, Lewinton S, Lockley WJ, Loreau O, Maddocks S, Marlière P, McEwen A, Moody TS, Morgan P, Roe SJ, Schenk DJ, Speed DJ, Stockman RA, Sumal K, Taran F, Thurston S, Waring M, Watters WHet al., 2015, Abstracts., J Labelled Comp Radiopharm, Vol: 58, Pages: 147-155

JOURNAL ARTICLE

Bultinck P, Cherblanc FL, Fuchter MJ, Herrebout WA, Lo Y-P, Rzepa HS, Siligardi G, Weimar Met al., 2015, Chiroptical Studies on Brevianamide B: Vibrational and Electronic Circular Dichroism Confronted, JOURNAL OF ORGANIC CHEMISTRY, Vol: 80, Pages: 3359-3367, ISSN: 0022-3263

JOURNAL ARTICLE

Curry E, Green I, Chapman-Rothe N, Shamsaei E, Kandil S, Cherblanc FL, Payne L, Bell E, Ganesh T, Srimongkolpithak N, Caron J, Li F, Uren AG, Snyder JP, Vedadi M, Fuchter MJ, Brown Ret al., 2015, Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, CLINICAL EPIGENETICS, Vol: 7, ISSN: 1868-7083

JOURNAL ARTICLE

Di Fruscia P, Zacharioudakis E, Liu C, Moniot S, Laohasinnarong S, Khongkow M, Harrison IF, Koltsida K, Reynolds CR, Schmidtkunz K, Jung M, Chapman KL, Steegborn C, Dexter DT, Sternberg MJE, Lam EW-F, Fuchter MJet al., 2015, The Discovery of a Highly Selective 5,6,7,8-Tetrahydrobenzo[4,5]thieno[ 2,3-d] pyrimidin-4(3H)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson's Disease Model, CHEMMEDCHEM, Vol: 10, Pages: 69-82, ISSN: 1860-7179

JOURNAL ARTICLE

Fuchter MJ, 2015, Young Career Focus: Dr. Matthew J. Fuchter (Imperial College London, UK), SYNTHESIS-STUTTGART, Vol: 47, Pages: A152-A155, ISSN: 0039-7881

JOURNAL ARTICLE

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