Licensing Portfolio - Small Molecules
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.
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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.
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In vivo Proof-of-Principle. A lead compound has been identified, which is a potent orally bioavailable inhibitor of FLT3 (IC50 35nM), Aurora-A (IC50 15nM) and Aurora-B (IC50 100nM) with minimal activity against a panel of over 100 kinases. The lead compound demonstrates potent cellular activity and robust oral
in vivo efficacy; it causes potent dose-dependent growth inhibition of MOLM-13 (AML) xenografts on oral delivery with concomitant biomarker modulation consistent with dual FLT3 and Aurora inhibition
in vivo. Moreover, the lead compound causes growth inhibition of MV4-11 (also AML) xenografts and overcomes resistance to selective FLT3 inhibition in MOLM13-MLN518- resistant human tumour xenografts. The lead compound also inhibits tumour growth in transgenic and primary transplant MYCN-driven neuroblastoma models and HCT116 colon tumour xenografts. A patent has been filed around the lead series; other valuable IP includes established biological assays, cellular and
in vivo PD biomarkers. Inhibitors with a selective FLT3 / Aurora-A inhibition profile are also available; these display high selectivity for Aurora-A versus Aurora-B in both biochemical and cellular assays (>480 fold). X-ray co-crystal structures that educate the binding mode and selectivity of this series have been obtained.
CRT is now seeking a commercial partner to further progress the FLT3 / pan-Aurora inhibitor compounds through preclinical development and/or progress the FLT3 / Aurora-A selective compounds to preclinical development candidates. Capacity and expertise to run first-in-man and paediatric clinical trials with PK/PD support could be available through The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.
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Selected Pre-clinical Candidate. 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.
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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.
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Lead Optimisation. Small molecule inhibitors of Autotaxin (ATX) have been discovered using an HTS approach and are currently undergoing lead optimisation. ATX cleaves choline from lysophosphatidylcholine (LPC) forming lysophosphatidic acid (LPA), a potent mitogen that has been implicated in the pathophysiology of cancer. ATX has been demonstrated to increase cell motility, neovascularization, proliferation and aggressiveness of tumours. It is upregulated in numerous tumour lineages (breast, glioblastoma, ovarian and prostate cancer).
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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. Elevated LIMK2 expression is associated with broad resistance to chemotherapeutic drugs. 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.
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Hit-to-Lead. A hit-to-lead stage programme is ongoing to discover small molecule inhibitors of PAK4. This kinase is involved in invasion and migration, anchorage independent growth, cell survival under stress, and signalling via cMet in a range of tumour types including prostate, pancreatic and colorectal. Two chemical series of drug-like patentable small molecules with low nM biochemical IC50s and
in vitro PD biomarker modulation are being investigated, with examples from one series showing selectivity for Group II over Group I PAKs. Medicinal chemistry is driven by the early input of structural biology, with a number of key compounds co-crystallised with the protein at high resolution. This programme also benefits from the expertise of academic collaborators in the field.
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HIt-to-Lead. This project aims at developing lead compounds with well-defined selectivity for CDK9, a promising therapeutic target in chronic lymphocytic leukaemia, as well as compounds with activity against CDK9 and other CDKs. Inhibition of CDK9 has been shown to overcome cellular resistance to apoptosis in CLL cells through inhibition of transcription. One promising series of hit compounds has been identified and patented and further medicinal chemistry efforts are underway.
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Hit-to-Lead. Cyclin-dependent kinases (CDKs) control major biological processes in cells. CDK7 regulates cell cycle progression through phosphorylation of CDKs and its regulation of PolII activity. Deregulation of cell cycle is a universal characteristic of cancer. Small molecule inhibition of CDK7 is anticipated to result in anti-proliferative and pro-apoptotic response in tumours. CRT is seeking a partner to (co)develop two series of CDK7 inhibitors currently in lead optimisation at the Imperial College Cancer Drug Design and Development Group. Compounds have low nM activity,
in vitro anti-tumour effect in a wider range of cancer cell lines and favourable
in vitro and
in vivo ADME properties.
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Hit-to-Lead. In cancer, one of the important tumour escape mechanisms is reactivation of telomerase expression via signal transduction pathways to circumvent cell mortality. Telomerase is expressed in > 85% of tumours from all types of cancer and its reactivation is thought to stabilise telomere length, compensating for telomere erosion and hence preventing senescence and apoptosis whilst providing unlimited proliferative capacity to malignant cells. Inhibition of telomerase in tumour cells is an attractive anticancer therapy which should disrupt telomere maintenance in malignant cells and its inhibition has been highlighted by Hanahan and Weinberg as one of the key therapeutic points to address one of the so called “hallmarks of cancer”. CRT has identified potent (< 100 nM) inhibitors of telomerase expression, which bind to novel targets in this pathway. CRT is seeking a commercial collaboration to progress these exciting compounds under a licensing or collaboration model.
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Hit-to-Lead. A series of isoform selective HDAC-2/3 inhibitors have been rationally designed for the treatment of AML and other N-CoR/SMRT related malignancies. A lead compound has been identified which has low nM biochemical potency, >500 fold selectivity against a range of other class I and II isoforms tested including HDAC-1; and <500nM IC50 in cell based phenotypic assays. A patent application on this lead series has recently been filed. Desirable
in vitro ADME and
in vivo PK properties have also been demonstrated. Biomarker development and
in vivo proof of efficacy studies are key future developmental milestones.
HDAC-3 is the only HDAC which is a “core” component of the N-CoR/SMRT repressor complexes. These complexes have been strongly implicated in AML. Moreover, HDAC-3 has also been implicated in the development of endometrial cancers. Thus, selective inhibition of HDAC-3 is an attractive strategy for the treatment of these diseases. Targeting specific HDAC isoforms known to play a central role in specific disease settings will lead to improved efficacy and tolerability as compared to pan inhibitors.
CRT is now seeking a commercial partner interested in pursuing a co-development or direct licensing arrangement.
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Small molecules as reagents have many and varied uses. Due to the ability to design molecules they can be more useful for research than some other molecules. We are pleased to present the datasheet for Lomeguatrib - a specific and highly potent inactivator of of the DNA repair protein MGMT and related mammalian proteins.
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