Chroma Therapeutics Limited

Glaxosmithkline Intellectual Property Development Limited

Singapore Volition Pte. Limited

Alan Hastings Drummond

Alan Hornsby Davidson

Sanjay Ratilal Patel

Stephen John Davies

Francesca Ann Mazzei

Alistair David Graham Donald

Kenneth William John Baker

David Festus Moffat

Alistair David Donald

David Festus Charles Moffat

Alastair David Graham Donald

Lindsay Jane Bawden

Lindsey Ann Needham

David Charles Festus Moffat

Francesca Ann Day

Andrew James Belfield

Elizabeth Ann Bone

Elisabeth Ann Bone

Kenneth William Baker

David Festus C Moffat

This invention relates to the diagnosis of disease conditions, such as cancer and autoimmune disease, by the analysis of cell-free nucleosomes in samples from individuals. Methods of the invention may include contacting cell-free nucleosomes from a biological fluid sample obtained from the individual with an antibody that binds specifically with a modified histone protein. Binding of the antibody to the nucleosomes is indicative that the individual has the disease condition.

Detection of histone modification in cell-free nucleosomes

Covalent conjugates of an &#x3b1;,&#x3b1;-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the &#x3b1;,&#x3b1;-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells, as in the following compound: 

Enzyme and receptor modulation using covalent conjugates of alpha,alpha-disubstituted glycine esters

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers, wherein Ris a carboxylic acid group (&#x2014;COOH), or an ester group which is hydrolysable by one or more intracellular carboxyesterase enzymes to a carboxylic acid group; Ris the side chain of a natural or non-natural alpha amino acid; Y is a bond, &#x2014;C(&#x2550;O), &#x2014;S(&#x2550;O)&#x2014;, &#x2014;C(&#x2550;O)O&#x2014;, &#x2014;C(O)NR&#x2014;, &#x2014;C(&#x2550;S)&#x2014;NR, &#x2014;C(&#x2550;NH)NRor &#x2014;S(&#x2550;O)NR&#x2014; wherein Ris hydrogen or optionally substituted C-Calkyl; Lis a divalent radical of formula -(Alk)(Q)(Alk)- wherein m, n and p are independently 0 or 1, Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula &#x2014;X-Q- or -Q-X&#x2014; wherein Xis &#x2014;O&#x2014;, S&#x2014; or NR&#x2014; wherein Ris hydrogen or optionally substituted C-Calkyl, and Qis an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, Alkand Alkindependently represent optionally substituted divalent C-Ccycloalkyl radicals, or optionally substituted straight or branched, C-Calkylene, C-Calkenylene, or C-Calkynylene radicals which may optionally contain or terminate in an ether (&#x2014;O&#x2014;), thioether (&#x2014;S&#x2014;) or amino (&#x2014;NR&#x2014;) link wherein Ris hydrogen or optionally substituted C-Calkyl; Xrepresents a bond; &#x2014;C(&#x2550;O); or &#x2014;S(&#x2550;O)&#x2014;; &#x2014;NRC(&#x2550;O)&#x2014;, &#x2014;C(&#x2550;O)NR&#x2014;, &#x2014;NRC(&#x2550;O)NR&#x2014;, &#x2014;NRS(&#x2550;O)&#x2014;, or &#x2014;S(&#x2550;O)NR&#x2014; wherein Rand Rare independently hydrogen or optionally substituted C-Calkyl; z is 0 or 1; A represents an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system wherein the radicals RRNH&#x2014;Y-L-X-[CH]&#x2014; and HONHCO-[LINKER]- are attached different ring atoms; and -[Linker]- represents a divalent linker radical linking a ring atom in A with the hydroxamic acid group CONIIOII, the length of the linker radical, from the terminal atom linked to the ring atom of A to the terminal atom linked to the hydroxamic acid group, is equivalent to that of an unbranched saturated hydrocarbon chain of from 3-10 carbon atoms. 

Enzyme inhibitors

Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers: wherein Q, V and W independently represent &#x2014;N&#x2550; or &#x2014;C&#x2550;; B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6). wherein the bond marked * is linked to the ring containing Q, V and W through -[Linker1]- and the bond marked ** is linked to A through -[Linker2]-; A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker1]- and -[Linker2]- independently represent a bond, or a divalent linker radical; and R is (a) a radical of formula RRCHNH&#x2014;Y-L-X&#x2014;(CH)&#x2014; or (b) a radical of formula R-L-Y&#x2014;(CH)&#x2014;.

Hydroxamates as inhibitors of histone deacetylase

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers: 

Compounds of formula (I) are inhibitors of histone deacetylase activity, and are useful in the treatment of, for example, cancers. 

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Abingdon, United Kingdom

Alan Hastings Drummond