Enabling the development of PKB inhibitors as novel cancer therapeutics
Submitting Institution
Institute of Cancer ResearchUnit of Assessment
Biological SciencesSummary Impact Type
TechnologicalResearch Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Summary of the impact
PKB (protein kinase B), also known as AKT, is an enzyme in the PI3
kinase/mTOR intracellular signalling pathway, which is deregulated in many
cancers. Professor David Barford's team at the ICR solved the crystal
structure of PKB03b2 using innovative protein engineering. The ICR has
licensed six international pharmaceutical companies with reagents to
enable them to begin PKB drug discovery programmes. The Barford team has
also used their structural biology expertise to advance the ICR's own PKB
inhibitor drug discovery programme. Two series of inhibitors were
developed that were licensed to AstraZeneca and Astex and are now both in
clinical trials.
Underpinning research
Professor David Barford (ICR Faculty) and his team published the results
of research, conducted between 1999 and 2002 in collaboration with a team
at the Friedrich Miescher Institute, on the crystal structure of the
enzyme PKB03b2 (also known as AKT2) (Refs 1 and 2). PKB was known to be a
key enzyme in the PI3 kinase/mTOR signalling pathway and is itself
mutated, overexpressed or amplified in certain cancers. As such it is a
potential target for anti-cancer drugs, but development of inhibitors of
PKB had been hindered by the lack of protein structural information. By
the early 2000s, it had been established that PKB is activated by two
phosphorylation events. While it was known that PDK1 phosphorylates
Thr309, the kinase responsible for phosphorylating Ser474 in the
hydrophobic motif had not been identified. Thus, there was no procedure
for generating activated PKB in vitro. The method of introducing a
sequence based on 'PIFtide' to mimic the structural consequences of Ser474
phosphorylation circumvented the need to phosphorylate Ser474, allowing
the Barford team to produce activated PKB for structural, biochemical and
functional studies. The innovative protein engineering used in the design
of the phospho-Ser474 mimetic constituted a major breakthrough in the
field. The ICR made the expression systems encoding the engineered protein
widely available to commercial companies and academic researchers.
The Barford team then collaborated with ICR Cancer Therapeutics teams led
by Dr Michelle Garrett (ICR Faculty, UoA1), Professor Paul Workman (ICR
Faculty, UoA1), Dr Ian Collins (ICR Faculty, UoA1) as lead chemist and Dr
Suzanne Eccles (ICR Faculty, UoA1). They began an in-house drug discovery
research programme in 2002, aimed at finding ATP competitive inhibitors of
PKB. In 2003, the ICR team began a collaboration with the UK company Astex
on this research programme. One innovative approach that the Barford and
Astex teams used was fragment based lead discovery (Ref 3). Another
innovative approach was a "back-soaking" method for obtaining
PKB03b2-ligand crystal structures (Ref 4).
Two fragment hits from the PKB screen were elaborated using
structure-based design and medicinal chemistry based on the Barford
protein structure information. Half of these medicinal chemistry research
studies and the majority of the biological research studies were
undertaken at the ICR, and these helped to validate PKB as a potential
oncology target. Each of the two hits led to the identification of a lead
chemical series and a number of publications resulted (Yap et al, 2012,
Clin Cancer Res 18, 3812-3823 and McHardy et al, 2010, J Med Chem 53,
2239-2249). One chemical series was licensed to AstraZeneca. The second
series was retained by Astex; this chemical series is distinct from the
first as it has a broader specificity and inhibits other AGC kinases,
which could contribute usefully to anticancer activity. In particular it
has potent Rho kinase activity and a biologically distinct profile (Yap et
al, 2012, Clin Cancer Res, 18, 3812-3823).
References to the research
All ICR authors are in bold and ICR team leaders/Faculty are in bold and
underlined.
1. Yang J, Cron P, Thompson V, Good VM, Hess D,
Hemmings BA, Barford D. 2002, Molecular Mechanism for the
Regulation of Protein Kinase B/Akt by Hydrophobic Motif Phosphorylation,
Mol Cell. 9 (6), 1227-1240. (http://dx.doi.org/10.1016/S1097-2765(02)00550-6)
2. Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford
D. 2002, Crystal structure of an activated Akt/protein kinase
B ternary complex with GSK3-peptide and AMP-PNP, Nat Struct Biol. 9,
940-944. (http://dx.doi.org/10.1038/nsb870)
3. Saxty G, Woodhead SJ, Berdini V, Davies TG, Verdonk ML, Wyatt PG,
Boyle RG, Barford D, Downham R, Garrett MD,
Carr RA. 2007, Identification of Inhibitors of Protein Kinase B Using
Fragment-Based Lead Discovery, J Med Chem. 50 (10), 2293-2296. (http://dx.doi.org/10.1021/jm070091b)
4. Davies TG, Verdonk ML, Graham B, Saalau-Bethell S, Hamlett CCF,
McHardy T, Collins I, Garrett MD, Workman P,
Woodhead SJ, Jhoti H, Barford DJ. 2007, A Structural
Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera, Mol Biol.
367 (3), 882-894. (http://dx.doi.org/10.1016/j.jmb.2007.01.004)
Details of the impact
The ICR has made a major impact on the international search for
inhibitors of PKB, a key signalling enzyme and a target for the
development of cancer therapeutics. This research has enabled a number of
pharmaceutical companies to advance their research programmes for the
development and commercialisation of novel drugs: currently, seven novel
PKB inhibitors are in clinical trials (ClinicalTrials.gov), two of which
are from the joint ICR and Astex PKB drug discovery programme.
Impacts on health
Two distinct drugs discovered by ICR and Astex are progressing
through clinical trials in the UK and overseas; patients are
benefiting by participating in these trials.
The ICR has discovered two series of PKB inhibitors in a collaborative
research programme with Astex. As a result, one series was licensed in a
commercial agreement with AstraZeneca and the lead drug, AZD5363, is
currently undergoing clinical trials at The Royal Marsden NHS Foundation
Trust (RM), The Christie (Manchester), the NKI (Netherlands) and in Japan,
involving a total of over 400 patients (ClinicalTrials.gov Identifiers:
NCT01226316, NCT01353781, NCT01625286, NCT01692262, NCT01895946) [1]. The
ICR has led on the first trial of AZD5363 and Dr Udai Banerji (ICR
Faculty) gave an oral presentation at AACR 2013 summarising its exciting
potential in the clinic in selected patients. Results of the first phase I
clinical trial of AZD5363 have reported both partial responses and stable
disease in patients harbouring mutations in PIK3CA or AKT1. This therefore
identifies these mutations as potential predictive biomarkers of response
for AZD5363. The lead compound of the second series, AT13148, which is
being developed by Astex, has different properties and could be useful in
a distinct patient group. This drug is also in clinical trial at RM,
enrolling 40 patients with advanced solid tumours (ClinicalTrials.gov
Identifier: NCT01585701) [2].
Impacts on commerce
The international PKB drug discovery effort has been facilitated by
ICR's work to solve the crystal structure.
The ICR solved the PKB crystal structure and published this work
(Research Refs 1 and 2 above) and in total, over 30 international
commercial companies, including many major pharmaceutical companies, have
cited the influence of these publications in their own publications (17
commercial companies have cited Ref 2 since 1 January 2008). This shows
that this work had an important impact on their in-house research
investment and endeavour (data from Web of Science). For example, since
2008 GSK has made major investment into developing PKB inhibitors as novel
therapeutics. Its lead product, GSK2110183, progressed into Phase II
clinical trials in 2009. GSK cited Reference 2 in their
publications [3, 4].
Two distinct drugs discovered by ICR and Astex are being
commercially developed
The drugs AZD5363 and AT13148, derived from chemical series discovered by
ICR and Astex, are being developed by AstraZeneca and Astex, respectively.
Both are in clinical trial. This has a commercial benefit to both these
companies by adding to their development pipeline and therefore increasing
shareholder value.
Industry is investing in pre-clinical research and clinical
research to develop PKB inhibitors in the UK (including at ICR and RM)
and overseas.
AstraZeneca and Astex are investing in the clinical research of AZD5363
and AT13148 respectively by conducting clinical trials. These drugs are
based on the chemical series discovered by the ICR. Companies such as GSK
that have cited ICR's underpinning research are investing in clinical
research worldwide (ClinicalTrials.gov lists several GSK2110183 clinical
trials, for example NCT01428492, NCT01531894, NCT01532700 and NCT01653912)
and seven novel PKB inhibitors are now being developed.
Sources to corroborate the impact
[1] http://investor.astx.com/releasedetail.cfm?ReleaseID=663984
[2] http://investor.astx.com/releasedetail.cfm?ReleaseID=663805
[3] Najafov A et al. 2011, Characterization of GSK2334470, a novel and
highly specific inhibitor of PDK1, Biochem J. 433, 357-369. (http://dx.doi.org/10.1042/BJ20101732)
[4] Heerding DA et al. 2008, 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. 51 (18),
5663-5679. (http://dx.doi.org/10.1021/jm8004527)