Pampisford, United Kingdom
Pampisford, United Kingdom

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Walton M.I.,Cancer Research UK Research Institute | Eve P.D.,Cancer Research UK Research Institute | Hayes A.,Cancer Research UK Research Institute | Valenti M.R.,Cancer Research UK Research Institute | And 16 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity. Experimental Design: Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay. Results: CCT244747 inhibited cellular CHK1 activity (IC50 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G2 arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma. Conclusion: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies. ©2012 AACR.


Walton M.I.,Cancer Research UK Research Institute | Eve P.D.,Cancer Research UK Research Institute | Hayes A.,Cancer Research UK Research Institute | Valenti M.,Cancer Research UK Research Institute | And 10 more authors.
Molecular Cancer Therapeutics | Year: 2010

Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G 1-S checkpoint control. This has led to the hypothesis that S and G2-M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G1-S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G2-M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC50 of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G2 arrest with an IC50 of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased γH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility. ©2010 AACR.


Patent
SAREUM Ltd | Date: 2013-02-04

The invention provides a compound having the formula (1): and salts thereof; wherein: R^(1 )is hydrogen or C_(1-2 )alkyl; andR^(2), R^(3 )and R^(4 )are the same or different and each is selected from hydrogen, C_(1-2 )alkyl, fluorine, chlorine, C_(1-2 )alkoxy and trifluoromethyl, provided that no more than two of R^(2), R^(3 )and R^(4 )are other than hydrogen. Also provided are pharmaceutical compositions containing the compounds and their use in medicine, and in particular in the treatment of cancer.


Patent
SAREUM Ltd | Date: 2014-10-31

The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1: provided that the sum of a and b is 0 or 1; T is O or NH Ar^(1 )is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R^(1); Ar^(2 )Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R^(2); and R^(1 )and R^(2 )are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.


Patent
SAREUM Ltd | Date: 2013-03-01

The invention provides a method of inhibiting a TYK2 kinase, which method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a compound having the formula (0): or a salt or stereoisomer thereof. The invention also provides a novel subset of compounds within formula (0) as well as pharmaceutical compositions containing them and their use in medicine.


Patent
SAREUM Ltd | Date: 2012-12-05

The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1: provided that the sum of a and b is 0 or 1; T is O or NH Ar^(1 )is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted en by one or more substituents R^(1); Ar^(2 )Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R^(2); and R^(1 )and R^(2 )are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.


Patent
Sareum Ltd | Date: 2014-06-03

The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1: provided that the sum of a and b is 0 or 1; T is O or NH Ar^(1 )is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R^(1); Ar^(2 )Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R^(2); and R^(1 )and R^(2 )are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.


Patent
Sareum Ltd | Date: 2013-09-04

The invention provides a compound which is an amide of the formula (2):R^(7) is selected from chlorine and fluorine;R^(3), R^(4), R^(5) and R^(6) are each independently selected from hydrogen, fluorine and chlorine;n is 0, 1 or 2;Q^(1) is selected from C(=O), S(=O) and SO_(2);A is absent or is NR^(2);R^(1) is selected from:- hydrogen;- an optionally substituted C_(1-6) non-aromatic hydrocarbon group; and- 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted;R^(2) is selected from hydrogen and C_(1-4) alkyl; orNR^(1)R^(2) forms an optionally substituted 4- to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen;with the provisos that:(i) no more than two of R^(3) to R^(6) are other than hydrogen; and(ii) when R^(7) and R^(6) are both fluorine, then one of R^(3) to R^(5) is chlorine or fluorine and/or R^(1)-A-Q^(1) is selected from ethylsulfonyl and isopropylsulfonyl. Also provided are pharmaceutical compositions containing the compounds and their therapeutic uses.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 148.38K | Year: 2013

The enzyme Fatty Acid Synthase (FASN) has been shown to be a key therapeutic target in cancer. Most normal cells acquire fatty acids from diet, so do not require or express FASN. By contrast, many types of cancer cell express high levels of FASN, and this expression is associated with poor patient prognosis. Sareum has discovered a novel series of inhibitors of FASN that are able to prevent cancer cell proliferation. The aim of this feasibility study is to investigate whether chemical modification of these inhibitors can improve their potency and stability, and thus warrant the investment in a full lead optimisation programme to develop candidate molecules for clinical trials in patients.


Patent
Sareum Ltd | Date: 2016-07-06

The invention provides a compound for use in a method for the diagnosis and treatment of a disease state or condition mediated by TYK2 kinase, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the kinase; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient an effective TYK2 inhibiting amount of the compound, wherein the compound has the formula (0):n is 0, 1 or 2;Ar^(1) is selected from an optionally substituted phenyl, pyridyl, thienyl and furanyl;Q^(1) is selected from C(=O), S(=O) and SO_(2);A is absent or is NR^(2);R^(1) is selected from hydrogen, an optionally substituted C_(1-6) non-aromatic hydrocarbon group and an optionally substituted 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms; orNR^(1)R^(2) forms an optionally substituted 4- to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen. The invention also provides compounds for use in the diagnosis and treatment of various autoimmune and inflammatory diseases through the inhibition of TYK2 kinase.

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