Chemical Biology

Led by:

Kilian Huber
Overview

The development of new medicines to treat diseases like cancer or inflammatory disorders is dependent on the identification of novel drug targets. Target selection requires an understanding of the functional relevance of a given protein in both physiological and pathophysiological conditions.

Our group combines chemistry and biology to generate small molecule tools, so-called “chemical probes” that enable studying the role of proteins as potential targets for drug discovery. Candidate targets may originate from genetic studies linking the expression or mutation of a selected gene to a particular disease, in vitro genetic screens such as RNA-interference or genome-editing (e.g. CRISPR, TALEN), compounds identified in phenotypic assays or drugs already in use.

To identify, explore and validate targets the Chemical Biology group uses a variety of different discovery approaches such as small molecule screens, biochemical assays, protein X-ray crystallography, chemical and protein-protein interaction proteomics, medicinal chemistry, RNAi as well as genome-editing alongside classical molecular and cellular biology techniques aiming at the development of new molecules that may provide leads for drug discovery.

 

Group Members

Laura Diaz Saez
PostDoc

Dr Laura Diaz Saez completed her Biochemistry degree at the Autonomous University of Madrid and obtained her PhD from the University of Dundee working on the assessment of potential antibacterial drug targets. She joined the Huber lab to work on the structural and biochemical characterisation of novel targets involved in cancer and inflammatory disorders.

Andrew Lewis
PostDoc

Originally from Swansea in Wales, Dr Andrew Lewis graduated with his PhD from the University of Cambridge in 2013 under the supervision of Prof Shankar Balasubramanian. During his PhD he worked on the synthesis and biological understanding of quinone containing natural products and their use as anticancer agents. Prior to this, Andrew read Natural Sciences at St Catharine's College, University of Cambridge completing his MSc with Prof Steven Ley working on the synthesis of novel hydrogen bond organocatalysts. From 2013 to 2016 Andrew worked as a postdoctoral fellow at the University of Toronto with Prof Patrick Gunning working on the design and synthesis of protein-protein interaction inhibitors and using chemical biological techniques to understand their mode of action. In 2016 Andrew joined the Huber group at the Target Discovery Institute where his current research involves the use of chemical biology and chemoproteomic techniques to identify novel drug targets for multiple myeloma.

Kathryn Pugh
PostDoc

Dr Kathryn Pugh completed her Mchem in Pharmaceutical Chemistry at the University of Leicester (UK) in 2009, where she completed her Masters project in the Glenn Burley group working on the preparation of DNA binding polyamides. From 2009 to 2013 she undertook a PhD in Chemical Biology at the University of Leicester (UK) in the labs of Prof Paul Cullis, Dr Glenn Burley (University of Strathclyde) and Prof Andrew Tobin. During this she studied kinases of the malarial parasite Plasmodium falciparum (Pf) to provide insight for new drug targets. In January 2014 Kathryn joined the Target Discovery Institute in the group of Prof Paul Brennan to develop chemoproteomic assays for the examination of interactions between small molecules and proteins. During this time she also worked on the quantification of modified nucleosides by LC-MS/MS with Prof Benedikt Kessler.

Cynthia Tallant
PostDoc (SGC-Tres Cantos Open Lab Foundation)

Dr Cynthia Tallant did her degree in Chemistry at the University Autonoma of Barcelona and obtained her PhD in Structural Biology and Enzymology at the IBMB-CSIC Science Park of Barcelona working on zinc metalloproteases. Cynthia has developed her career as a research scientist in the UK for more than four years in Chemical Biology Drug Discovery groups at the University of Cambridge and since 2013 at the SGC-Oxford. Her work comprises the production and characterization of therapeutic proteins or enzymes, biochemical assay screening with compound libraries and structural determination of ligand-bound complexes with epigenetic and kinase targets. Inn 2015 Cynthia won a fellowship from the Tres Cantos Open Lab Foundation supported by GSK to work on the development of novel therapeutics to treat Malaria.

Srikannathasan Velupillai
PostDoc

Dr Srikannathasan (Kannan) Velupillai completed his PhD in Structural Biology and Enzymology at the University of St Andrews and University of East Anglia working on the Bordertella pertussis lipopolysachcharide biosynthetic pathway. He then joined the group of Professor James Naismith to investigate Rhamnose biosynthetic pathway enzymes. In 2009, Kannan joined GSK, Stevenage as a Senior Scientist working on the structure and function of a new class of antibacterials funded by the Defense Threat Reduction Agency and the Wellcome Trust as part of the “Drug Discovery Programme in Relation to Gram Negative Bacteria”. In 2012, Kannan moved back to Dundee University and worked on several projects focussing on the Bacterial Type VI secretion system, Tryptophan metabolic pathway enzymes (Bill Hunter Lab) and  IRAK2 (IL-1R-associated kinase (IRAK) family 2) and various kinase projects (Philip Cohen lab). In October 2014, Kannan joined the SGC where his current focus has been on protein production and structural studies of epigenetic drug targets.

Jenny Ward
PostDoc

Jenny Ward completed her first degree (MChem) in Chemistry at the University of Oxford in 2011, having completed her Masters research in the synthesis and biological evaluation of non-inositol based ligands for the IP3 receptor under the supervision of Dr Stuart Conway. From 2011 to 2016 she undertook an MRes and PhD in Chemical Biology at the ICB-CDT, Imperial College London. Under the supervision of Prof Ed Tate and Prof Eric Lam, her research involved the design and proteomic profiling of activity-based probes for studying cellular ubiquitination machinery. In June 2016 Jenny joined the Huber group at the Target Discovery Institute, where her current research focuses on the chemoproteomic identification of novel drug targets in multiple myeloma.

Sarah Blair-Reid
Research Assistant

Dr Sarah Blair-Reid has experience in both academic and industrial research institutes, in the UK and USA.  Having completed her PhD in molecular and cellular biology at the University of Birmingham, this was followed by two post-doctoral research assistant positions in the field of DNA damage and repair.  Withinthe Huber group Sarah is a Research Assistant in Cellular Biology, involved in the generation of CRISPR mutant cell lines, and carrying out cell based assays. 

Catherine Rogers
Research Assistant

Dr Catherine Rogers completed her degree in Biochemistry degree at the University of Warwick and then undertook a PhD with AstraZeneca and the University of Nottingham, in the School of Pharmacy. She then spent two years working as a postdoctoral research associate in the EPSRC Centre for Innovative Manufacturing in Regenerative Medicine at the University of Nottingham, before joining the SGC in 2013. Her work comprises of establishing and running cellular target engagement assays.

Ioanna Panagakou
Laboratory Technician

Ioanna Panagakou completed her Bachelor’s degree in Chemistry at the University of Crete and then specialized in Biochemistry for her Master thesis. She then moved to the UK to do her PhD in Cell Biology at the University of Edinburgh. In 2016, she joined the Huber group as a lab technician.

Vicki Gamble
Useful Links

Group Publications

2016

Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk.
Sdelci, S; Lardeau, CH; Tallant, C; Klepsch, F; Klaiber, B; Bennett, J; Rathert, P; Schuster, M; Penz, T; Fedorov, O; Superti-Furga, G; Bock, C; Zuber, J; Huber, KV; Knapp, S; Müller, S; Kubicek, S;
Nature Chemical Biology. 2016 12:504-510. doi:
PMID: 27159579

Profiling of Small Molecules by Chemical Proteomics.
Huber, KV; Superti-Furga, G;
Methods in Molecular Biology. 2016 1394:211-218. doi:
PMID: 26700051

2015

Proteome-wide drug and metabolite interaction mapping by thermal-stability profiling.
Huber, KV; Olek, KM; Müller, AC; Tan, CS; Bennett, KL; Colinge, J; Superti-Furga, G;
Nature Methods. 2015 12:1055-1057. doi:
PMID: 26389571

Target profiling of an antimetastatic RAPTA agent by chemical proteomics: Relevance to the mode of action
Babak, MV; Meier, SM; Huber, KVM; Reynisson, J; Legin, AA; Jakupec, MA; Roller, A; Stukalov, A; Gridling, M; Bennett, KL; Colinge, J; Berger, W; Dyson, PJ; Superti-Furga, G; Keppler, BK; Hartinger, CG;
Chemical Science. 2015 6:2449-2456. doi: 10.1039/c4sc03905j
PMID:

SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.
Rebsamen, M; Pochini, L; Stasyk, T; de Araújo, ME; Galluccio, M; Kandasamy, RK; Snijder, B; Fauster, A; Rudashevskaya, EL; Bruckner, M; Scorzoni, S; Filipek, PA; Huber, KV; Bigenzahn, JW; Heinz, LX; Kraft, C; Bennett, KL; Indiveri, C; Huber, LA; Superti-Furga, G;
Nature. 2015 519:477-481. doi:
PMID: 25561175

A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis.
Fauster, A; Rebsamen, M; Huber, KV; Bigenzahn, JW; Stukalov, A; Lardeau, CH; Scorzoni, S; Bruckner, M; Gridling, M; Parapatics, K; Colinge, J; Bennett, KL; Kubicek, S; Krautwald, S; Linkermann, A; Superti-Furga, G;
Cell Death and Disease. 2015 6:e1767-. doi:
PMID: 25996294

2014

Further Evaluation of Pro-Atherogenic and Anti-Angiogenic Effects of Nilotinib in Mice and in Patients with Ph-Chromosome plus CML
Hadzijusufovic, E; Albrecht-Schgoer, K; Huber, K; Grebien, F; Eisenwort, G; Schgoer, W; Kaun, C; Herndlhofer, S; Theurl, M; Cerny-Reiterer, S; Hoermann, G; Sperr, WR; Rix, U; Sadovnik, I; Jilma, B; Schernthaner, GH; Wojta, J; Wolf, D; Superti-Furga, G; Kirchmair, R; Valent, P;
Blood. 2014 124:-. doi:
PMID:

Nilotinib exerts proatherogenic and growth-inhibitory effects on endothelial cells: a potential mechanism underlying drug-related vasculopathy in Ph plus CML
Hadzijusufovic, E; Albrecht-Schgoer, K; Huber, K; Grebien, F; Eisenwort, G; Schgoer, W; Ghanim, V; Sadovnik, I; Kaun, C; Herndlhofer, S; Theurl, M; Cerny-Reiterer, S; Hoermann, G; Jilma, B; Sperr, WR; Rix, U; Wojta, J; Wolf, D; Superti-Furga, G; Kirchmair, R; Valent, P;
Oncology Research and Treatment. 2014 37:300-300. doi:
PMID:

The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.
Winter, GE; Radic, B; Mayor-Ruiz, C; Blomen, VA; Trefzer, C; Kandasamy, RK; Huber, KV; Gridling, M; Chen, D; Klampfl, T; Kralovics, R; Kubicek, S; Fernandez-Capetillo, O; Brummelkamp, TR; Superti-Furga, G;
Nature Chemical Biology. 2014 10:768-773. doi:
PMID: 25064833

Building and exploring an integrated human kinase network: global organization and medical entry points.
Colinge, J; César-Razquin, A; Huber, K; Breitwieser, FP; Májek, P; Superti-Furga, G;
Journal of Proteomics. 2014 107:113-127. doi:
PMID: 24704859

Evaluating the Promiscuous Nature of Tyrosine Kinase Inhibitors Assessed in A431 Epidermoid Carcinoma Cells by Both Chemical- and Phosphoproteomics
Giansanti, P; Preisinger, C; Huber, KVM; Gridling, M; Superti-Furga, G; Bennett, KL; Heck, AJR;
ACS Chemical Biology. 2014 9:1490-1498. doi: 10.1021/cb500116c
PMID:

Inhibition of NAD+-dependent histone deacetylases (sirtuins) causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi.
Veiga-Santos, P; Reignault, LC; Huber, K; Bracher, F; De Souza, W; De Carvalho, TM;
Parasitology (Cambridge). 2014 141:814-825. doi:
PMID: 24670415

Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.
Huber, KV; Salah, E; Radic, B; Gridling, M; Elkins, JM; Stukalov, A; Jemth, AS; Göktürk, C; Sanjiv, K; Strömberg, K; Pham, T; Berglund, UW; Colinge, J; Bennett, KL; Loizou, JI; Helleday, T; Knapp, S; Superti-Furga, G;
Nature. 2014 508:222-227. doi:
PMID: 24695225

Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission.
Kern, S; Agarwal, S; Huber, K; Gehring, AP; Strödke, B; Wirth, CC; Brügl, T; Abodo, LO; Dandekar, T; Doerig, C; Fischer, R; Tobin, AB; Alam, MM; Bracher, F; Pradel, G;
PLoS One. 2014 9:e105732-. doi:
PMID: 25188378

2013

ELUCIDATING THE MOLECULAR MECHANISM OF ACTION OF CANCER DRUGS IN THE SECOND DECADE OF THE NEW MILLENNIUM
Superti-Furga, G; Winter, G; Bigenzahn, J; Radic, B; Colinge, J; Bennett, K; Kubicek, S; Zuber, J; Brummelkamp, T; Huber, K;
Experimental Hematology. 2013 41:S9-S9. doi:
PMID:

Experimental characterization of the human non-sequence-specific nucleic acid interactome.
Dürnberger, G; Bürckstümmer, T; Huber, K; Giambruno, R; Doerks, T; Karayel, E; Burkard, TR; Kaupe, I; Müller, AC; Schönegger, A; Ecker, GF; Lohninger, H; Bork, P; Bennett, KL; Superti-Furga, G; Colinge, J;
Genome Biology: biology for the post-genomic era. 2013 14:R81-. doi:
PMID: 23902751

Regulation of pro-angiogenic tissue factor expression in hypoxia-induced human lung cancer cells.
Eisenreich, A; Zakrzewicz, A; Huber, K; Thierbach, H; Pepke, W; Goldin-Lang, P; Schultheiss, HP; Pries, A; Rauch, U;
Oncology Reports: an international journal devoted to fundamental and applied research in oncology. 2013 30:462-470. doi:
PMID: 23604472

Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma.
Weirauch, U; Beckmann, N; Thomas, M; Grünweller, A; Huber, K; Bracher, F; Hartmann, RK; Aigner, A;
Neoplasia. 2013 15:783-794. doi:
PMID: 23814490

2012

Target/s Identification Approaches – Experimental Biological Approaches
Huber, K; Superti-Furga, G; Winter, GE;
. 2012 :94-110. doi: 10.1039/9781849734912-00094
PMID:

7,8-dichloro-1-oxo-β-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes.
Huber, K; Brault, L; Fedorov, O; Gasser, C; Filippakopoulos, P; Bullock, AN; Fabbro, D; Trappe, J; Schwaller, J; Knapp, S; Bracher, F;
Journal of Medicinal Chemistry. 2012 55:403-413. doi: 10.1021/jm201286z
PMID: 22136433

2011

After the grape rush: sirtuins as epigenetic drug targets in neurodegenerative disorders.
Huber, K; Superti-Furga, G;
Bioorganic and Medicinal Chemistry. 2011 19:3616-3624. doi:
PMID: 21306906

Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing.
Fedorov, O; Huber, K; Eisenreich, A; Filippakopoulos, P; King, O; Bullock, AN; Szklarczyk, D; Jensen, LJ; Fabbro, D; Trappe, J; Rauch, U; Bracher, F; Knapp, S;
Chemistry and Biology. 2011 18:67-76. doi: 10.1016/j.chembiol.2010.11.009
PMID: 21276940

2010

A Versatile Synthesis of 3-Substituted 4-Cyano-1,2,3,4-tetrahydro-1-oxo-beta-carbolines
Huber, K; Kast, O; Bracher, F;
Synthesis: journal of synthetic organic chemistry. 2010 :3849-3854. doi: 10.1055/s-0030-1258282
PMID:

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers.
Brault, L; Gasser, C; Bracher, F; Huber, K; Knapp, S; Schwaller, J;
Haematologica: the hematology journal. 2010 95:1004-1015. doi:
PMID: 20145274

Novel 3-arylideneindolin-2-ones as inhibitors of NAD+ -dependent histone deacetylases (sirtuins).
Huber, K; Schemies, J; Uciechowska, U; Wagner, JM; Rumpf, T; Lewrick, F; Süss, R; Sippl, W; Jung, M; Bracher, F;
Journal of Medicinal Chemistry. 2010 53:1383-1386. doi:
PMID: 20030343

2007

Cytotoxic hybrids between the aromatic alkaloids bauerine C and rutaecarpine
Huber, K; Bracher, F;
Zeitschrift fuer Naturforschung, Section B: A Journal of Chemical Sciences. 2007 62:1313-1316. doi:
PMID:

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