Inhibitors of LIMK1 and LIMK2 (New)
Licensing or Collaboration
Hit-to-Lead/Lead Optimisation
LIMK1 and LIMK2 are emerging targets for both cancer and ocular disease. They are up-regulated in metastatic breast and prostate tumours. Over-expression has been demonstrated to increase tumour cell migration and invasion and to increase tumour growth, angiogenesis and metastasis in vivo. Conversely, abrogation of LIMK function results in decreased breast cancer cell motility and formation of osteolytic bone lesions in an animal model of invasion. Down-regulation of LIMK1 has been demonstrated to reduce inflammation in a mouse model of ocular surgery and small molecule inhibition or genetic deletion of LIMK2 is effective in reducing intraocular pressure in mouse models, a key risk factor in disease progression in glaucoma. CRT has developed two series of novel, potent, ATP-competitive small molecule inhibitors of LIMK1/2 which (i) inhibit the ability of cancer cells to invade in multiple authentic cancer cell invasion assays, and (ii) sensitise tumour cells to cell death induced by chemotherapeutic agents.
CRT is now seeking a commercial partner to progress these exciting compounds under a licensing or co-development model.
Contact: Dr Laura Fletcher, lfletcher@CancerTechnology.com
 Further details can be accessed here
Senectus Therapeutics Limited (New)
Investment or Collaboration
Assay Development & Early Screening
Senectus Therapeutics Ltd is a CRT led company focused on understanding and then drugging cellular senescence. Senectus is founded on a hand-picked consortium of key UK scientists and their rapidly advancing understanding of cellular senescence in cancer biology. In conceiving Senectus, the primary objective was to bring together world leading CRUK expertise in mammalian cellular senescence along with new and advanced technologies in cell engineering and imaging to generate an improved understanding of senescence, a toolbox of high content screening techniques, reagents and tools. Ultimately, the outcome of the initiative will be identification of critical paths in cellular senescence, development of screens for compounds modulating senescence and small molecules and target leads for drug development and pathway manipulation.
Senectus has secured $1M in seed funding and is currently seeking further investment. Further financing could take the form of equity or programme-specific collaborative investment.
Contact: Dr Anthony Brown, abrown@CancerTechnology.com
Further details can be accessed here
Inhibitors of CDC7 (New)
CRT Discovery Laboratories Project
Lead Optimisation
Cdc7 serine/threonine kinase plays an essential role in assembly of the pre-replicative complex (that renders origins ‘licensed’ for DNA synthesis) and G1/S transition through phosphorylation of MCM proteins (replicative helicases). Inhibition of Cdc7 has been demonstrated to selectively induce cell death in tumours versus induce a reversible cell cycle arrest in non-malignant cells. Two series of novel, selective small molecule inhibitors which exhibit low nM activity against Cdc7 and cellular efficacy (apoptosis) have been developed. Biomarker and phenotypic assays have been established. CRT is now seeking a commercial partner to progress this programme under a licensing or co-development model.
Contact: Dr Tanya Moore, tmoore@CancerTechnology.com
Chk1 Inhibitor Programme
In Vivo - Proof-of-Principle
Novel compound series with nM activity against the Chk1 cell-cycle checkpoint kinase have been identified starting from a combined crystallographic-bioassay template screen. The lead series demonstrates Chk1 cellular activity, has good ADMET properties, and has been subject to ongoing medicinal chemistry to optimise cellular and in vivo activity. The programme also comprises novel IP, established biological assays and co-crystallographic expertise.
CRT is now offering prospective commercial partners global rights to the Chk1 programme on an exclusive basis for all fields.
Contact: Dr Phil Masterson, pmasterson@CancerTechnology.com
Further details can be accessed here
Chk2 Inhibitor Programme
Lead Optimisation
A potent and selective compound series with low nM activity against the Chk2 cell-cycle checkpoint kinase has been developed. This programme currently comprises novel patented compounds, established biological assays, co-crystallographic methods to support and inform ongoing medicinal chemistry and novel synergy studies. CRT is now seeking a commercial partner interested in pursuing a co-development or direct licensing arrangement.
Contact: Dr Laura Fletcher, lfletcher@CancerTechnology.com
Further details can be accessed here
CYP26 Inhibitor Programme (New)
Hit-to-Lead
Selective small molecule CYP26 inhibitors have been developed with impressive activity in a microsomal CYP26 assay and in cell-based ATRA metabolism assays. CYP26 inhibitors have utility in enhancing the activity of therapeutic forms of retinoic acid, by preventing their in vivo metabolism and limiting therapy resistance. Retinoic acid derivatives such as ATRA and 13cisRA are used clinically to reverse malignant growth, but suffer from onset of resistance. The small molecules identified are able to enhance the anti-proliferative effects of ATRA/13cisRA in a neuroablastoma cell panel.
Contact: Dr Tanya Moore, tmoore@CancerTechnology.com
Novel Inhibitors of Aurora Kinase
Lead Optimisation
A potent series of compounds with low nM activity against Aurora-A and Aurora-B has been discovered. Compounds from this series have demonstrated good cellular activity as well as robust oral in vivo activity in a colon tumour xenograft model. Lead optimisation studies have successfully focussed on optimising PK properties whilst maintaining potency and cell based activity. The programme also comprises novel IP including a patented lead series, established biological assays, cellular and in vivo PD biomarkers. Studies to identify patient populations most likely to respond to Aurora inhibition have revealed a strong signature in colon cancer cell lines (microarray and cell line sensitivity data). In addition, a follow-on programme focusing on Aurora-A selective inhibitors has been initiated. This programme has identified a lead compound with low nM activity against Aurora-A and selectivity in both biochemical (>350 fold) and cellular (>60 fold) assays for Aurora-A versus Aurora-B. In addition, X-ray co-crystal structures that elucidate the binding mode of the series have been obtained. CRT is now seeking a commercial partner to further progress the pan-Aurora and/
or the Aurora-A selective programmes.
Contact: Dr Anne Horgan, ahorgan@CancerTechnology.com
Further details can be accessed here
Novel Histone Deacetylase (HDAC) Inhibitors
Hit-to-Lead
A series of HDAC inhibitors with a novel selectivity profile and very promising in vitro activity and ADME properties is under development. One of the series is an isoform specific HDAC3 inhibitor with low nM activity, 2 fold selectivity over HDAC2 and >500 fold selectivity against a range of other Class 1 and 2 isoforms tested, including HDAC1.
HDAC3 is the only HDAC which is a “core” component of the N-CoR/SMRT repressor complexes. These complexes have been strongly implicated in acute myeloid leukaemia (AML). Moreover, HDAC3 has also been implicated in the development of endometrial cancers. Thus, selective inhibition of HDAC3 is an attractive strategy for the treatment of these diseases. Targeting specific HDAC isofoms known to play a central role in specific disease settings will lead to improved efficacy and tolerability as compared to pan inhibitors.
Contact: Dr Surbhi Gupta, sgupta@CancerTechnology.com
Inhibitors of the MDM2-p53 Protein-Protein Interaction
Hit-to-Lead/Lead Optimisation
A novel series of potent MDM2-p53 inhibitors that display a cellular response consistent with the activation of p53. Significant SAR has been generated around the isoindolinone scaffold and structural data is available from an ongoing academic collaboration. The compounds are the subject of two filed patent applications. CRT is now seeking a commercial partner interested in collaborating with the academic groups to further progress this programme.
Contact: Dr Tanya Moore, tmoore@CancerTechnology.com
Further details can be accessed here
Axl Kinase Inhibitors
CRT Discovery Laboratories Project
Hit-to-Lead
A major high-throughput screening campaign has led to the identification of potent inhibitors of Axl, a transmembrane type 1 receptor tyrosine kinase that has been shown to have oncogenic and angiogenic properties in vitro and in vivo in a number of tumour types. Axl is also up-regulated in primary tumour tissue, and has been associated with drug resistance. Two chemical series with <50nM activity in biochemical assays are being progressed through the hit-to-lead phase. The compounds demonstrate activity in cellular biomarker assays and phenotypic assays.
Contact: Dr Theo Balasas, tbalasas@CancerTechnology.com
Further details can be accessed here
Hypoxic Response Inhibitors
Hit-to-Lead
Novel derivatives of ketoglutarate have been developed and demonstrated to reduce HIF-1 alpha levels in cells under hypoxic conditions. In vivo proof-of-principle efficacy demonstrated with protoype compounds. The compounds may also be applicable to the treatment of cancers in patients predisposed to neoplasia through mutations within the Krebs tricarboxylic acid cycle (TCA cycle).
Contact: Dr Roisin NicAmhlaoibh, rnicamhlaoibh@CancerTechnology.com
Further details can be accessed here
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