Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Peter Ballard is active.

Publication


Featured researches published by Peter Ballard.


Cancer Discovery | 2014

AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer

Darren Cross; Susan Ashton; Serban Ghiorghiu; Cath Eberlein; Caroline A. Nebhan; Paula Spitzler; Jonathon P. Orme; M. Raymond V. Finlay; Martine J. Mellor; Gareth Hughes; Amar Rahi; Vivien Jacobs; Monica Red Brewer; Eiki Ichihara; Jing Sun; Hailing Jin; Peter Ballard; Katherine Al-Kadhimi; Rachel Rowlinson; Teresa Klinowska; Graham Richmond; Mireille Cantarini; Dong-Wan Kim; Malcolm R Ranson; William Pao

UNLABELLED First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.


Journal of Medicinal Chemistry | 2014

Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor

M. Raymond V. Finlay; Mark J. Anderton; Susan Ashton; Peter Ballard; Paul A. Bethel; Matthew R. Box; Robert Hugh Bradbury; Simon Brown; Sam Butterworth; Andrew Campbell; Christopher G. Chorley; Nicola Colclough; Darren Cross; Gordon S. Currie; Matthew Grist; Lorraine Hassall; George B. Hill; Daniel S. James; Michael James; Paul D. Kemmitt; Teresa Klinowska; Gillian M. Lamont; Scott Lamont; Nathaniel G. Martin; Heather L. McFarland; Martine J. Mellor; Jonathon P. Orme; David Perkins; Paula Perkins; Graham Richmond

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.


Clinical Cancer Research | 2016

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

Peter Ballard; James W.T. Yates; Zhenfan Yang; Dong-Wan Kim; James Chih-Hsin Yang; Mireille Cantarini; Kathryn Pickup; Angela Jordan; Mike J Hickey; Matthew Grist; Matthew R. Box; Peter Johnström; Katarina Varnäs; Jonas Malmquist; Kenneth S. Thress; Pasi A. Jänne; Darren Cross

Purpose: Approximately one-third of patients with non–small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. Experimental Design: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). Results: Osimertinib demonstrated greater penetration of the mouse blood–brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. Conclusions: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130–40. ©2016 AACR.


Journal of Medicinal Chemistry | 2013

Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases.

Matt Addie; Peter Ballard; David Buttar; Claire Crafter; Gordon S. Currie; Barry R. Davies; J.E. Debreczeni; Hannah Dry; Philippa Dudley; Ryan Greenwood; Paul D. Johnson; Jason Grant Kettle; Clare Lane; Gillian M. Lamont; Andrew G. Leach; Richard William Arthur Luke; Jeff Morris; Donald J. Ogilvie; Ken Page; Martin Pass; Stuart E. Pearson; Linette Ruston

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.


Cancer Research | 2016

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

Hazel M. Weir; Robert Hugh Bradbury; Mandy Lawson; Alfred A. Rabow; David Buttar; Rowena Callis; Jon Owen Curwen; Camila de Almeida; Peter Ballard; Micheal Hulse; Craig S. Donald; Lyman Feron; Galith Karoutchi; Philip A. MacFaul; Thomas A. Moss; Richard A. Norman; Stuart E. Pearson; Michael Tonge; Gareth Davies; Graeme Walker; Zena Wilson; Rachel Rowlinson; Steve Powell; Claire Sadler; Graham Richmond; Brendon Ladd; Ermira Pazolli; Anne Marie Mazzola; Celina D'Cruz; Chris De Savi

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.


Bioorganic & Medicinal Chemistry Letters | 2008

Novel 3-alkoxy-1H-pyrazolo[3,4-d]pyrimidines as EGFR and erbB2 receptor tyrosine kinase inhibitors.

Richard Ducray; Peter Ballard; Bernard Barlaam; Mark Hickinson; Jason Grant Kettle; Donald J. Ogilvie; Catherine B. Trigwell

Novel 4-anilino-1H-pyrazolo[3,4-d]pyrimidines have been synthesized and evaluated in vitro for erbB2 and EGFR kinase inhibition. A representative compound displaying oral bioavailability in rat and dog illustrates the potential of this series to provide orally active erbB2 inhibitors.


Journal of Medicinal Chemistry | 2015

Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.

Chris De Savi; Robert Hugh Bradbury; Alfred A. Rabow; Richard A. Norman; Camila de Almeida; David M. Andrews; Peter Ballard; David Buttar; Rowena Callis; Gordon S. Currie; Jon Owen Curwen; Christopher D. Davies; Craig S. Donald; Lyman Feron; Helen Gingell; Steven C. Glossop; Barry R. Hayter; Syeed Hussain; Galith Karoutchi; Scott Lamont; Philip A. MacFaul; Thomas A. Moss; Stuart E. Pearson; Michael Tonge; Graeme Walker; Hazel M. Weir; Zena Wilson

The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.


Drug Metabolism Reviews | 2012

The right compound in the right assay at the right time: an integrated discovery DMPK strategy

Peter Ballard; Patrick Brassil; Khanh Bui; Hugues Dolgos; Carl Petersson; Anders Tunek; Peter Webborn

The high rate of attrition during drug development and its associated high research and development (R&D) cost have put pressure on pharmaceutical companies to ensure that candidate drugs going to clinical testing have the appropriate quality such that the biological hypothesis could be evaluated. To help achieve this ambition, drug metabolism and pharmacokinetic (DMPK) science and increasing investment have been deployed earlier in the R&D process. To gain maximum return on investment, it is essential that DMPK concepts are both appropriately integrated into the compound design process and that compound selection is focused on accurate prediction of likely outcomes in patients. This article describes key principles that underpin the contribution of DMPK science for small-molecule research based on 15 years of discovery support in a major pharmaceutical company. It does not aim to describe the breadth and depth of DMPK science, but more the practical application for decision making in real-world situations.


Xenobiotica | 2008

Determination of microsome and hepatocyte scaling factors for in vitro/in vivo extrapolation in the rat and dog

R. Smith; R. D. O. Jones; Peter Ballard; H. H. Griffiths

1. In vivo clearance predictions from in vitro assays require scaling factors to relate the concentrations of hepatocytes or microsomal protein to the intact liver. 2. The aims were to measure the variability in scaling factors for Wistar rat and beagle dog for which the literature is particularly scarce and determine any sex differences. 3. Scaling factors were determined by comparing the cytochrome P450 (P450) content in hepatocytes or microsomes against the P450 content of fresh liver homogenate. The use of fresh homogenate is recommended as freezing can increase contamination and affect the P450 assay. 4. Meangeo hepatic microsomal concentrations in Wistar rats were 61 mg g−1 liver (95% confidence interval (CI); 47–75 mg g−1 liver) and in beagle dogs 55 mg g−1 liver (95% CI = 48–62 mg g−1 liver). Meangeo hepatocellularity was 163 × 106 cells g−1 liver for Wistar rats (95% CI = 127–199 × 106 cells g−1 liver) and 169 × 106 cells g−1 liver (95% CI = 131–207 × 106 cells g−1 liver) for beagle dogs. The data generated in this study indicate a consistency in scaling factors between rat and dog. No sex differences were observed.


Bioorganic & Medicinal Chemistry Letters | 2011

Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

Robert Hugh Bradbury; Neil J. Hales; Alfred A. Rabow; Graeme Walker; David G. Acton; David M. Andrews; Peter Ballard; Nigel Brooks; Nicola Colclough; Alan Girdwood; Urs Hancox; Owen Jones; David Jude; Sarah A. Loddick; Andrew Austen Mortlock

Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.

Collaboration


Dive into the Peter Ballard's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge