Open, Non-Randomized, Single Centre Phase I Study to Assess the Metabolism, Excretion and Pharmacokinetics of a Single Oral 100 mg Dose of [14C]-AZD2281 (KU-0059436) in Patients With Advanced or Metastatic Solid Tumours Refractory to Standard Treatments

Open, non-randomized, radiolabelled, single centre study designed to characterize the metabolism, excretion and pharmacokinetics of a single oral dose of 100 mg [14C]-radiolabelled AZD2281 (KU-0059436) in patients with advanced or metastatic solid tumours.

开始日期2008-04-01

申办/合作机构

AstraZeneca PLC

[+1]

EUCTR2006-006459-10-DE / Not yet recruiting临床2期

A phase II, open-label, non-comparative, international, multicentre study to assess the efficacy and safety of KU 0059436 given orally twice daily in patients with advanced BRCA1- or BRCA2-associated ovarian cancer. - ICEBERG

开始日期2007-07-18

申办/合作机构

KuDOS Pharmaceuticals Ltd.

NCT00516438 / Completed临床1期

A Phase I, Open-Label, Study of the Safety and Tolerability of KU-0059436 and Topotecan in the Treatment of Patients With Advanced Solid Tumours

The purpose of this study is to identify a safe and tolerable dose of the drug KU-0059436 that can be given in combination with topotecan chemotherapy in patients with advanced solid tumours

开始日期2007-07-01

申办/合作机构

AstraZeneca PLC

[+1]

100 项与 KuDOS Pharmaceuticals Ltd. 相关的临床结果

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0 项与 KuDOS Pharmaceuticals Ltd. 相关的专利（医药）

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项与 KuDOS Pharmaceuticals Ltd. 相关的文献（医药）

2016-10-15·Cancer research1区 · 医学

The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models

1区 · 医学

Article

作者: Martin, Niall M.B. ; Bradbury, Robert H. ; Jones, Louise ; Oplustil O'Connor, Lenka ; Knights, Charlotte ; Evers, Bastiaan ; O'Connor, Mark J. ; Rudge, David ; Ting, Attilla ; Caldecott, Keith W. ; Odedra, Rajesh ; Brown, Henry ; Lau, Alan ; Rulten, Stuart L. ; Pajic, Marina ; Rottenberg, Sven ; Jaspers, Janneke E. ; Cranston, Aaron N. ; Jonkers, Jos

Abstract:

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084–94. ©2016 AACR.

2013-08-22·Journal of medicinal chemistry1区 · 医学

1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity

1区 · 医学

Article

作者: Shea, K. ; Golding, Bernard T. ; Smith, Graeme C. M. ; Newell, David R. ; Hardcastle, Ian R. ; Griffin, Roger J. ; Frigerio, Mark ; Menear, Keith A. ; Thommes, Pia ; Saravanan, Kappusamy ; Richardson, Caroline J. ; Cano, Céline ; Ting, Attilla ; Bailey, Chris ; Curtin, Nicola J. ; Bardos, Julia ; Hummersone, Marc G.

Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.

2010-12-23·Journal of medicinal chemistry1区 · 医学

DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

1区 · 医学

Article

作者: Newell, David R. ; Spittle, Ben ; Hardcastle, Ian R. ; Golding, Bernard T. ; Cockcroft, Xiao-Ling ; Griffin, Roger J. ; Bailey, Christine ; Frigerio, Mark ; Smith, Graeme C. M. ; Menear, Keith A. ; Barbeau, Olivier R. ; Knights, Charlotte ; Cano, Céline ; Richardson, Caroline J. ; Hummersone, Marc G. ; Curtin, Nicola J. ; Duggan, Heather

Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy , J. J. J. ; Golding , B. T. ; Griffin , R. J. ; Hardcastle , I. R. ; Richardson , C. ; Rigoreau , L. ; Smith , G. C. M. Bioorg. Med. Chem. Lett. 2004 , 14 , 6083 - 6087) as a potent inhibitor (IC₅₀ = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH₂)(n)NR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki-Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure-activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC₅₀ = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.

项与 KuDOS Pharmaceuticals Ltd. 相关的新闻（医药）

2023-05-22

·GlobeNewswire-Health Care

PharmEnable Closes $7.5M Financing led by MP Healthcare to Develop Next Generation of Small Molecule Drugs to Treat Cancer and Neurological Diseases

$7.5M Pre-Series A financing led by new investor MP Healthcare, the venture arm of Mitsubishi Tanabe Pharma Group. Existing investors Cambridge Enterprise, University of Cambridge Enterprise Fund VIII, managed by Parkwalk Advisors Heyford Trust, o2h Ventures, Martlet Capital, Arrowfield Capital, Wren Capital and experienced life sciences angel investors including Jonathan Milner also participated PharmEnable has developed a proprietary drug discovery platform that focuses on chemical novelty, diversity and 3-dimensionality Funds will allow PharmEnable to advance and expand its portfolio of wholly owned and co-discovery projects around challenging targets in cancer and neurology Expanded Board of Directors includes Dr Jeffrey Moore and Dr Keith Blundy, both of whom bring significant biotech and pharmaceutical industry experience PharmEnable, a drug discovery company focused on chemical novelty, diversity and complexity, announces it has closed a Pre-Series A investment round of $7.5M to develop the next generation of small molecule drugs against disease areas of high clinical need. The funding round was led by MP Healthcare Venture Management (MPH), the venture arm of Mitsubishi Tanabe Pharma Group, with additional participation from existing investors including Cambridge Enterprise, the commercialisation arm of the University of Cambridge, University of Cambridge Enterprise Fund VIII, managed by Parkwalk Advisors, Heyford Trust, o2h Ventures, Martlet Capital, Arrowfield Capital, Wren Capital and life science experienced angel investors including Jonathan Milner. The funds will be used to advance and expand PharmEnable’s portfolio of wholly owned and co-discovery projects across oncology and neurology targets, as well as supporting further platform R&D. PharmEnable uses its proprietary platform to discover targeted therapies with the aim of replicating the specificity of biologics, but with improved efficacy, absorption and distribution properties enabled by custom-designed oral small molecules, which are also easier to scale and manufacture. The Company’s approach combines advanced medicinal chemistry with state-of-the-art AI technology, allowing it to unlock challenging biological targets by mapping unexplored chemical space. This approach delivers novel proprietary candidate drug molecules with the required 3-dimensional structure elements that lead to improved selectivity and ultimately reduce attrition rates. The aim is to develop therapies that are highly effective with fewer side effects to treat diseases with a high clinical need. PharmEnable has a pipeline of wholly owned oncology programmes, as well as ongoing co-discovery projects with several pharma and biotech companies, including a partnership with Sosei Heptares to unlock novel drug candidates for neurological disease. The wholly owned programmes focus on addressing some of the key challenges in oncology such as tumour penetration and overcoming resistance mechanisms, through designing novel, complex small molecules with improved selectivity and carefully balanced properties. Alongside the investment, PharmEnable’s Board has been expanded with Dr Jeffrey Moore joining as a Board Director, representing MP Healthcare. Dr Keith Blundy has replaced Dr Christine Martin as an Investor Director on behalf of Cambridge Enterprise. Both bring significant pharma and biotech experience. Dr Jeffrey Moore is President of MP Healthcare and has been working in the biotech sector for 25 years, both as an investor and in operating roles at Millennium Pharmaceuticals and Scriptgen. Until recently Dr Keith Blundy was the CEO of STORM Therapeutics and prior to that Chief Executive of Cancer Research Technology Ltd (CRT), the commercial arm of Cancer Research UK. He was formerly a director of KuDOS Pharmaceuticals Ltd, Mission Therapeutics, Cancer Therapeutics Pty and Inivata Ltd. CEO of PharmEnable Dr Hannah Sore said, “At PharmEnable, we believe that everyone deserves safe and effective treatments, and we are committed to applying the principles chemical novelty, diversity and 3-dimensionality to design powerful new small molecule drugs. I am delighted that MP Healthcare has led our Pre-Series A to enable our mission to deliver life-changing medicines to patients who need them. “I am pleased to welcome the highly experienced Dr Jeffrey Moore and Dr Keith Blundy to our Board and look forward to working our team, our Board and our investors to deliver novel therapeutics for the most challenging disease areas, ultimately making a difference to patients’ lives.” Dr Jeffrey Moore, Board Director of PharmEnable on behalf of new investor MP Healthcare, said, “MPH is dedicated to supporting next generation products and technologies to increase the options available to patients with significant unmet medical needs. We continue to explore novel modalities of treatment, including biotherapeutics, nucleic acid medicines and cell therapies. However, we continue to recognize the clear benefits that small molecules can offer. After an extensive review of available companies and technologies, we concluded that PharmEnable’s robust technology platform was best positioned to effectively explore novel chemical space and deliver the next generation of small molecule therapeutics.” About PharmEnable PharmEnable is a Cambridge (UK) based biotech developing the next generation of small molecule drugs, with a focus on novelty, diversity and 3-dimensionality. The company’s interdisciplinary approach integrates advanced medicinal chemistry expertise and cutting-edge AI/computational methods to deliver novel therapeutics for diseases with high clinical need. PharmEnable’s proprietary drug discovery platform provides a powerhouse for generating novel chemical entities against challenging targets. It models drug targets to identify their key molecular interactions, and map and expand the novel chemical space that can modulate a specific target. Advanced medicinal chemistry expertise guides the development of synthesizable, complex and 3-dimensional small molecules, increasing specificity and reducing off-target effects. Its vision is to reproduce the specificity of biologics in the powerful and scalable form of a small molecule. PharmEnable’s mission is to deliver life-changing medicines. Its world-class team works across a range of disease areas where drug specificity is a significant challenge, such as cancer and neurological disease. It has a pipeline of wholly owned pre-clinical projects, as well as ongoing co-discovery projects with several pharma and biotech companies, including Sosei Heptares. The company is backed by life science experienced angle and venture investors including MP Healthcare Venture Management (the venture arm of Mitsubishi Tanabe Pharma Group), Cambridge Enterprise, University of Cambridge Enterprise Funds, Heyford Trust, O2H Ventures, Martlet Capital, Arrowfield Capital and Wren Capital. The content above comes from the network. if any infringement, please contact us to modify.

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