WO2024100402A1 - Composés chimères ciblant la protéolyse - Google Patents

Composés chimères ciblant la protéolyse Download PDF

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WO2024100402A1
WO2024100402A1 PCT/GB2023/052922 GB2023052922W WO2024100402A1 WO 2024100402 A1 WO2024100402 A1 WO 2024100402A1 GB 2023052922 W GB2023052922 W GB 2023052922W WO 2024100402 A1 WO2024100402 A1 WO 2024100402A1
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compound
pharmaceutically acceptable
optionally
acceptable salt
formula
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PCT/GB2023/052922
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Andrew Fielding
Morgan GADD
Marine AUBLETTE
Amanda Cristina Godot THOMAZ
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University Of Lancaster
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to proteolysis-targeting chimeras (PROTAC) compounds. More particularly, the present invention relates to PROTAC compounds for targeting kinesin family member C1 (KIFC1). Further still, the present invention relates to PROTAC compounds for use in the treatment of cancer. Background Approximately 1 in 3 individuals will develop cancer during their lifetime. The standard of care for cancer patients is chemotherapy and/or radiotherapy. Both of these treatments typically have undesirable side effects for the patient, such as nausea and fatigue, in part due to the therapy’s lack of specificity for cancer cells. In severe circumstances, side effects may cause the patient to discontinue the treatment.
  • PROTAC proteolysis-targeting chimeras
  • KIFC1 a kinesin-14 family member, localises to the mitotic spindle during mitosis and promotes spindle pole-focusing.
  • KIFC1-mediated pole-focusing drives both the clustering of amplified centrosomes and the clustering of acentrosomal spindle poles.
  • KIFC1 promotes cancer cell survival by binding to Survivin and preventing its degradation, therefore protecting cells from apoptosis.
  • KIFC1 has also been linked to microtubule crosslinking, minus-end directed movement, and tethering of microtubule minus ends to centrosomes via binding CEP215/CDK5RAP2.
  • KIFC1 Experiments employing siRNA knockdown of KIFC1 support KIFC1 having a prominent role in cancer proliferation. KIFC1 therefore plays a prominent role in the proliferation and growth of cancer cells. Centrosome amplification has been observed in tumours and cell lines of many cancer types, often correlating with aggressive disease and poor patient survival. Targeting KIFC1 across a broad range of cancers is therefore an attractive avenue for cancer treatment. For example, patients with triple negative breast cancer (TNBC) have poor overall prognosis and survival, and TNBC cells have been shown to rely on KIFC1 activity for their survival. KIFC1 is therefore a promising target in the treatment of cancer. It is therefore desirable to develop therapies which target KIFC1 for the treatment of cancer.
  • TNBC triple negative breast cancer
  • Some small molecules which inhibit KIFC1 activity have been developed, including AZ82, CW069 and SR31527.
  • the low potency and limited specificity of these compounds for cancer cells limits their use in research and their clinical applications.
  • studies have demonstrated that these compounds do bind specifically to KIFC1, induce multipolar spindles in cells with centrosome amplification, and inhibit the growth of cancer cells.
  • previous studies have shown that AZ82 effectively promotes centrosome de-clustering and as a consequence increases the occurrence of multipolar mitosis of cells bearing multiple centrosomes.
  • AZ82 has low potency for KIFC1 and displays non-selective cytotoxic effects. Improved small molecule compounds targeting KIFC1 are therefore required.
  • KIFC1 can be degraded in vitro using proteolysis targeting chimera (PROTAC) compounds and KIFC1 is unexpectedly a suitable target protein for PROTAC-mediated degradation.
  • PROTAC proteolysis targeting chimera
  • the data provided by the inventors demonstrates that surprisingly KIFC1 is expressed and localised in cancer cells where there is adequate expression of E3 ligases to effect PROTAC-mediated degradation of KIFC1.
  • the present invention provides a significant contribution to the art in providing, for the first time, a means of degrading KIFC1 in cancer.
  • the present inventors have provided, for the first time, a completely new therapeutic class of compound, namely PROTAC compounds for degrading KIFC1.
  • PROTAC compounds for degrading KIFC1 Prior to the inventors providing this new class of therapeutic compound, compounds for degrading KIFC1 in cells were unknown.
  • the present invention therefore represents a promising new therapeutic class of compound for the treatment of cancer. More particularly, the disclosure of the present invention describes for the first time PROTAC compounds which are capable of degrading KIFC1 in a highly selective manner. The inventors have demonstrated that the compounds of the present invention are extremely efficient in degrading KIFC1, and are more effective in treating cancer cells than known inhibitors of KIFC1.
  • the compounds of the present invention are extremely potent inducers of apoptosis in cancer cells, with no significant adverse effects on normal cells.
  • the advantageous anti- cancer activity of the compounds of the invention is at least in part achieved by mimicking the binding mode of a KIFC1 ligand, for example the KIFC1 ligand AZ82.
  • the advantageous anti-cancer activity of the compounds of the invention is at least in part achieved by mimicking the binding mode of a ligand capable of binding an E3 ligase, for example a Cereblon (CRBN) ligand.
  • the inventors propose that it is the provision of compounds which can concurrently act as a ligand capable of binding KIFC1, and as a ligand capable of binding E3 ligase, more particularly CRBN, that provides the advantageous anti- cancer activity of the present invention.
  • the inventors propose that the spatial orientation of the ligand capable of binding the E3 relative to ligand capable of binding KIFC1 plays an important role in providing the desirable activity of the present compounds.
  • the inventors postulate that, in some embodiments, the number of atoms in the linker group R is important to PROTAC-mediated KIFC1 degradation as described in more detail herein.
  • the linker group R provides sufficient flexibility and length to allow for the ligand capable of binding KIFC1 to bind to KIFC1 as well as the ligand capable of binding an E3 ligase (preferably CRBN) to bind to the E3 ligase. This allows the E3 ligase to be recruited to KIFC1 which in turn allows for ubiquitination / proteasomal degradation of KIFC1.
  • a compound according to Formula (I), or a pharmaceutically acceptable salt thereof L 1 -R-L 2 ; Formula (I) wherein L 1 is a ligand capable of binding kinesin family member C1 (KIFC1); L 2 is a ligand capable of binding E3 ligase; and R is a linker group with a chain length having an integer of at least 3 atoms. R may be a linker group with a chain length having an integer of from 3 to 20 atoms.
  • R may be a linker group with a chain length having an integer of from 3 to 12 atoms, optionally from 3 to 10 atoms, optionally still from 4 to 8 atoms, further optionally from 5 to 7 atoms (e.g.6 atoms).
  • R may be selected from optionally substituted C3-C20 alkylene, optionally substituted C 3 -C 20 haloalkylene, optionally substituted C 3 -C 20 heteroalkylene, optionally substituted C3-C20 alkenylene, optionally substituted C3-C20 haloalkenylene, optionally substituted C3-C20 heteroalkenylene; optionally substituted C3-C20 alkynylene; optionally substituted C3-C20 haloalkynylene and optionally substituted C3-C20 heteroalkynylene.
  • R may be selected from optionally substituted C3-C12 alkylene, optionally substituted C3-C12 haloalkylene, optionally substituted C3-C12 heteroalkylene, optionally substituted C3-C12 alkenylene, optionally substituted C3-C12 haloalkenylene, optionally substituted C3-C12 heteroalkenylene; optionally substituted C3-C12 alkynylene; optionally substituted C3-C12 haloalkynylene and optionally substituted C3-C12 heteroalkynylene.
  • R has at least 1 atom in the chain length that forms part of an optionally substituted carbocyclic or optionally substituted heterocyclic group.
  • the optionally substituted carbocyclic or optionally substituted heterocyclic group is selected from optionally substituted C3-C7 cycloalkyl, optionally substituted C5- C8 cycloalkenyl, optionally substituted C3-C7 heterocycloalkyl, optionally substituted C5- C8 heterocycloalkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • the optionally substituted carbocyclic or optionally substituted heterocyclic group forms part of the chain length having an integer of from 3 to 20 atoms, optionally 3 to 12 atoms, that provides linker group R.
  • the carbocyclic group which in this embodiment is a phenyl moiety, forms part of the R linker group and contributes three carbon atoms to the chain length.
  • the phenyl group contributes the atoms labelled 3, 4 and 5 to the chain length, as depicted.
  • R may be C 3 -C 20 alkylene having the general formula -(CH 2 ) n - where n is an integer from 3 to 20.
  • R may be C 3 -C 12 alkylene having the general formula -(CH 2 ) n - where n is an integer from 3 to 12, optionally from 4 to 10, optionally still from 4 to 9.
  • n may be an integer from 4 to 7, 5 to 8, optionally from 6 to 7 (e.g. n is 6).
  • m is 2 to 9, optionally still from 4 to 8.
  • m may be an integer from 5 to 7 (e.g. m is 6).
  • R may be C 5 -C 20 heteroalkylene having the general formula -XCH 2 (CH 2 OCH 2 ) p CH 2 X- where p is an integer from 1 to 6, and each X is independently absent or is independently selected from O, NH, COO and CONH.
  • R may be C 5 -C 12 heteroalkylene having the general formula -XCH 2 (CH 2 OCH 2 ) p CH 2 X- where p is an integer from 1 to 3, and each X is independently absent or is independently selected from O, NH, COO and CONH.
  • p is from 2 to 3.
  • R is polyethylene glycol.
  • R may be C5-C12 heteroalkylene having the general formula -(CH2)2(OCH2CH2)p1- where p1 is an integer from 1 to 3.
  • R may be C 5 -C 12 heteroalkylene having the general formula -(CH2)2(OCH2CH2)p1- where p1 is an integer from 1 to 3. In embodiments, p is from 1, 2 or 3.
  • R may be a C5-C20 heteroalkylene having the general formula -XCH2(CH2NHCH2)qCH2X- where q is an integer from 1 to 6, and each X is independently absent or is independently selected from O, NH, COO and CONH.
  • R may be a C5-C12 heteroalkylene having the general formula -XCH2(CH2NHCH2)qCH2X- where q is an integer from 1 to 3, and each X is independently absent or is independently selected from O, NH, COO and CONH.
  • R is a linker group defined with a chain length having an integer that exceeds 20 (i.e. is 21 or greater) in the above formulae are not encompassed within the scope of the embodiments described.
  • R may be a carbon chain, optionally a C 3 -C 20 carbon chain.
  • R may be a carbon chain, optionally a C 3 -C 12 carbon chain, optionally still a C 4 -C 11 carbon chain, further optionally a C5-C10 carbon chain.
  • R may be a C4-C8 carbon chain, optionally a C4-C7 carbon chain or optionally a C5-C7 carbon chain (e.g. a C 6 carbon chain).
  • the carbon chain is alkylene or alkenylene.
  • R is n- alkylene or n-alkenylene, that is to say a linear alkyl group or alkenyl group.
  • R is propylene.
  • R is butylene.
  • R is pentylene.
  • R is hexylene. In embodiments, R is heptylene. In embodiments, R is octylene. In embodiments, R is nonylene. In embodiments, R is decylene. In embodiments, R is undecylene. In embodiments, R is dodecylene. In embodiments, R is polyethylene. In embodiments, R is polypropylene. In embodiments, R is polyethylene glycol. In embodiments, R is polyethylenimine.
  • R may be defined by the formula R’(CH 2 ) n R’’ and the compound is according to formula (II) or a pharmaceutically acceptable salt thereof: R' R'' L 1 n L 2 ; Formula (II) wherein R’ and R’’ are each independently selected from CH 2 , O, S, NH, CO, COO and CONH; and n is an integer from 1 to 20.
  • R’ and R’’ are each independently selected from CH 2 , O, S, NH, CO, COO, CONH, SO 2 N and SO 2 ; and n is an integer from 1 to 20
  • R may be defined by the formula R’(CH 2 ) n R’’ and the compound is according to formula (II) or a pharmaceutically acceptable salt thereof: R' R'' L 1 n L 2 ; Formula (II) wherein R’ and R’’ are each independently selected from CH2, O, S, NH, CO, COO and CONH; and n is an integer from 1 to 10.
  • R’ and R’’ are each independently selected from CH 2 , O, S, NH, CO, COO, CONH, SO 2 N and SO 2 ; and n is an integer from 1 to 10.
  • n may be an integer from 2 to 9, optionally n may be an integer from 3 to 8, optionally still from 4 to 7 (e.g. n is 4, n is 5 or n is 6).
  • R’ and R’’ are each independently absent and n is an integer from 3 to 20.
  • R’ and R’’ are each independently absent and n is an integer from 3 to 12. In such embodiments, n may be an integer from 4 to 11, optionally from 5 to 10, optionally still from 6 to 9, further optionally from 7 to 8.
  • R’ and R’’ may be absent and n may be an integer that is 6.
  • L 1 may be defined according to formula (III): Formula (III) wherein W and V are each independently selected from O, S, NH, CO, COO and CONH; R 1 and R 2 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkenyl, C 1 -C 6 heteroalkenyl, C 1 -C 6 alkynyl, C 1 -C 6 haloalkynyl, C 1 -C 6 heteroalkynyl, -ONHR 6 and - OR 6 ; R 3 , R 4 and R 5 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C
  • W is selected from CO, COO and CONH.
  • W is CONH.
  • V is selected from CO, COO and CONH.
  • V is CO or CONH.
  • R1 and R2 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, C1-C6 haloalkenyl, C1-C6 heteroalkenyl, C1-C6 alkynyl, C1-C6 haloalkynyl, C1-C6 heteroalkynyl, -ONHR6 and - OR6.
  • R1 and R2 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, and -OR6.
  • R1 and R2 are each independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 alkenyl, C1-C6 alkynyl and -OR6.
  • R1 and R2 are each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl and -OR 6 .
  • R 1 and R 2 are each C 1 -C 6 alkyl.
  • R 3 , R 4 and R 5 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxyl.
  • R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxyl, suitably C 1 -C 6 haloalkyl (such as -CF 3 ).
  • R 3 and R 5 are H.
  • R 3 and R 5 are H and R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxyl, suitably C 1 -C 6 haloalkyl (such as -CF 3 ).
  • R 6 is selected from H and C 1 -C 6 alkyl.
  • R 6 is H, methyl or ethyl.
  • phenyl or pyridyl suitably phenyl.
  • X is N and Y is CH. In another embodiment, X is CH and Y is N.
  • L1 is defined according to formula (IIIa): Formula (IIIa) where R 1 , R 2 , R 3 , R 4 , R 5 , Q, X and Y are as defined in any of the embodiments above.
  • L 1 is defined according to formula (IIIb): Formula (IIIb) where R1, R2, R3, R4, R5 are as defined in any of the embodiments above.
  • L1 may be defined according to formula (IV): Formula (IV) wherein Z is selected from O, NH and S; X is CH and Y is N, or X is N and Y is CH; and R 1 -R 5 , W and V are as defined in Formula (III) and embodiments thereof.
  • L 1 may be defined according to formula (IVa): Formula (IVa) wherein Z is selected from O, NH and S; X is CH and Y is N, or X is N and Y is CH; and R 1 -R 5 are as defined in Formula (III) and embodiments thereof.
  • L 1 may be according to Formula (V): Formula V wherein R 1 and R 2 are each independently C 1 -C 6 alkyl; and R 4 is C 1 -C 6 haloalkoxy.
  • L 1 may be according to Formula (VI): ; Formula (VI) L 1 may be selected from AZ82, CW069, SR31527, or derivatives thereof.
  • a radical of L 1 is provided, typically a monovalent radical, wherein said radical forms a covalent bond with a radical of linker group R as defined herein.
  • L 1 is AZ82
  • a radical of AZ82 is contemplated which forms a covalent bond with a radical of linker group R as defined herein.
  • L 1 -R is or where the dotted bond indicated the point of attachment to L2.
  • L2 is an E3 ubiquitin ligase binding moiety capable of binding to von Hippel-Lindau (VHL) E3 ligase or cereblon (CRBN) E3 ligase.
  • L 2 is an E3 ubiquitin ligase binding moiety of formula VIIa1: (VIIa1), where R M2e is F or CN, RM 2b is hydrogen or methyl (suitably S-methyl), and where the wavy line denotes the point of attachment to R.
  • R M2e is F and RM 2b is hydrogen.
  • L2 is an E3 ubiquitin ligase binding moiety of formula VIIa2: (VIIa2), where R M1b is H or (S)-methyl, and where the wavy line denotes the point of attachment to R.
  • L2 may be a ligand capable of binding CRBN, optionally wherein the ligand capable of binding CRBN is selected from thalidomide, pomalidomide, or lenalidomide, or a derivative thereof; preferably wherein the CRBN ligand is pomalidomide or a derivative thereof.
  • L2 may be according to formula (VIIb): Formula (VIIb) wherein is a 6-membered carbocyclic or heterocyclic group when U’ is CH or CH 2 , or is a 5-membered carbocyclic or heterocyclic group when U’ is absent; X’ and Y’ are each independently CH 2 , CO or absent; Z’ is CH 2 or absent; W’ is NH, CH2 or O; and R7 is optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C 3 -C 6 cycloalkenyl or optionally substituted C 3 - C6 heterocycloalkenyl, optionally wherein R7 is optionally substituted C3-C6 heterocycloalkyl selected from pyrolidinyl, piperidinyl, and cyclic imidyl, optionally still wherein R 7 is a cyclic imidyl selected from pyrolidinedi
  • At least two of X’, Y’ and Z’ are present. In other words, at least one of X’, Y’ and Z’ is not absent.
  • Y’ and X’ are each independently CH 2 or CO. For instance, if Z’ is absent, Y’ is CO and X’ is CO. In embodiments, if X’ is absent, Y’ is CH 2 or CO and Z’ is CH 2 . In embodiments, if Y’ is absent, X’ is CH 2 or CO and Z’ is CH 2 .
  • R7 is piperidinedioneyl; Y’ is CH2, CO or absent; X’ is CO; W’ is NH, CH2 or O; and Z’ is absent, wherein L2 is according to formula (IX): O HN O Y ' N W' O Formula (IX) In embodiments, Y’ is CO and W’ is NH, and L2 is according to formula (X): In another embodiment, L2 is selected from: , where the wavy bond indicates the point of attachment to R.
  • the compound is according to formula (XI): Formula (XI) wherein n is an integer from 3 to 12, optionally from 4 to 11, optionally still from 4 to 10, optionally still from 4 to 8, optionally still from 5 to 10, further optionally from 6 to 9.
  • n may be 4, or n may be 5.
  • n is 6.
  • n is 7.
  • the compound is according to formula (XI) and n is from 3 to 20 suitably from 3 to 10; suitably, 3 to 8; suitably 4 to 8.
  • the compound is according to Formula (XII) Formula (XII) wherein n is an integer from 3 to 12, optionally from 4 to 11, optionally still from 4 to 10, optionally still from 4 to 8, optionally still from 5 to 10, further optionally from 6 to 9.
  • n may be 4, or n may be 5.
  • n is 6.
  • n is 7.
  • the compound is according to Formula (XII) and n is from 3 to 20.
  • the compound is: ; or ; or .
  • the compound is (2R)-N-(6- ⁇ [2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3- dihydro-1H-isoindol-4-yl]amino ⁇ hexyl)-2-[(5-methyl-4-propylthiophen-2-yl)formamido]-3- ⁇ 6-[3-(trifluoromethoxy)phenyl]pyridin-3-yl ⁇ propenamide, or enantiomers thereof.
  • L1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (III):
  • W and V are each independently selected from O, S, NH, CO, COO and CONH;
  • L1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to to formula (IIIb):
  • R 1 and R 2 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkenyl, C 1 -C 6 heteroalkenyl, C 1 -C 6 alkynyl, C 1 -C 6 haloalkynyl, C 1 -C 6 heteroalkynyl, -ONHR 6 and - OR6;
  • R3, R4 and R5 are each independently selected from H, halogen,
  • L1-R-L2 there is a compound according to formula (I), or a pharmaceutically acceptable salt thereof: L1-R-L2; Formula (I) wherein: L 1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (V): Formula (V) wherein R1 and R2 are each independently C1-C6 alkyl; and R4 is C1-C6 haloalkoxy; L 2 is a ligand capable of binding E3 ligase and is according to the formula (IX) wherein Y’ is CH 2 or CO; and W’ is NH, CH 2 or O: Formula (IX); and R is a linker group, optionally a linker group with a chain length having an integer of from 3 to 20 atoms, optionally from 3 to 12 atoms; suitably from 3 to 10; suitably, 3 to 8; suitably 4 to 8.
  • L 1 is a ligand capable of binding kinesin family member C1 (KIFC
  • L 1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (V): ;
  • R 1 and R 2 are each independently C 1 -C 6 alkyl; and R4 is C1-C6 haloalkoxy;
  • L2 is a ligand capable of binding E3 ligase and is according to the formula (IX) wherein Y’ is CH2 or CO; and W’ is NH, CH2 or O: Formula (IX); and R is a linker group with a chain length having an integer of from 3 to 20 atoms, wherein R is: C3-C20 alkylene having the general formula -(CH2)n- where n is an integer from 3 to 20; or C3-C20 heteroalkylene having the general formula -X(
  • L1-R-L2 there is a compound according to formula (I), or a pharmaceutically acceptable salt thereof: L1-R-L2; Formula (I) wherein: L 1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (V): Formula (V) wherein R1 and R2 are each independently C1-C6 alkyl; and R4 is C1-C6 haloalkoxy; L2 is a ligand capable of binding E3 ligase and is according to the formula (IX) wherein Y’ is CH2 or CO; and W’ is NH, CH2 or O: Formula (IX); and R is a linker group with a chain length having an integer of from 3 to 12 atoms, wherein R is: C 3 -C 12 alkylene having the general formula -(CH 2 ) n - where n is an integer from 3 to 12; or C 3 -C 12 heteroalkylene having the general formula -X
  • L 1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (V): Formula (V) wherein R1 and R2 are each independently C1-C6 alkyl; and R4 is C1-C6 haloalkoxy; L2 is a ligand capable of binding E3 ligase and is according to the formula (IX) wherein Y’ is CH2 or CO; and W’ is NH, CH2 or O: Formula (IX); and R is a linker group with a chain length having an integer of from 3 to 20 atoms, wherein R is C 3 -C 20 alkylene having the general formula -(CH 2 ) n - where n is an integer from 3 to 20, suitably from 3 to 10; suitably, 3 to 8; suitably 4 to
  • L 1 is a ligand capable of binding kinesin family member C1 (KIFC1) and is according to formula (V): ; Formula (V) wherein R1 and R2 are each independently C1-C6 alkyl; and R4 is C1-C6 haloalkoxy; L2 is a ligand capable of binding E3 ligase and is according to the formula (IX) wherein Y’ is CH2 or CO; and W’ is NH, CH2 or O: Formula (IX); and R is a linker group with a chain length having an integer of from 3 to 12 atoms, wherein R is C3-C12 alkylene having the general formula -(CH2)n- where n is an integer from 3 to 12, suitably from 3 to 10; suitably, 3 to 8; suitably 4 to 8.
  • the invention provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition of the invention according to this aspect may be provided in the pharmaceutical composition of the invention according to this aspect.
  • the invention provides a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, or a pharmaceutical composition according to any aspect or embodiment disclosed herein, for use as a medicament.
  • any specific embodiment of the compounds and pharmaceutically acceptable salts of the formulae of the invention described herein may be provided for use as a medicament according to this aspect.
  • the invention provides a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, or a pharmaceutical composition according to any aspect or embodiment disclosed herein, for use in the treatment of cancer.
  • the cancer may be a solid tumour.
  • the solid tumour may be any solid tumour, for instance, melanoma, glioblastoma, pancreatic cancer and breast cancer.
  • the cancer is breast cancer, optionally triple negative breast cancer.
  • the cancer is melanoma, optionally uveal melanoma.
  • any specific embodiment of the compounds and pharmaceutically acceptable salts of the formulae of the invention described herein may be provided for use in the treatment of cancer according to this aspect.
  • a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, or a pharmaceutical composition as disclosed herein, in the manufacture of a medicament.
  • the medicament may be for use in the treatment of cancer.
  • the cancer may be a solid tumour.
  • the solid tumour may be any solid tumour, for instance, melanoma, glioblastoma, pancreatic cancer and breast cancer.
  • the cancer is breast cancer, optionally triple negative breast cancer.
  • the cancer is melanoma, optionally uveal melanoma.
  • any specific embodiment of the compounds and pharmaceutically acceptable salts of the formulae of the invention described herein may be provided in the manufacture of a medicament according to this aspect.
  • a method for treating a mammal comprising the step of administering to said mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, or a pharmaceutical composition as disclosed herein, to said mammal.
  • a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any aspect or embodiment disclosed herein, or a pharmaceutical composition as disclosed herein, to said mammal.
  • any specific embodiment of the compounds and pharmaceutically acceptable salts of the formulae of the invention described herein may be provided according to this aspect.
  • a method for the treatment of cancer in a mammal comprising the step of administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as defined according to any aspect or embodiment disclosed herein, or a pharmaceutically acceptable composition as defined herein, to the mammal in need thereof.
  • the cancer may be a solid tumour.
  • the solid tumour may be any solid tumour, for instance, melanoma, glioblastoma, pancreatic cancer and breast cancer.
  • the cancer is breast cancer, optionally triple negative breast cancer.
  • the cancer is melanoma, optionally uveal melanoma.
  • any specific embodiment of the compounds and pharmaceutically acceptable salts of the formulae of the invention described herein may be provided in the method according to this aspect.
  • a method of degrading KIFC1 comprising recruiting an E3 ligase to KIFC1, optionally wherein the E3 ligase is a CRBN ligase.
  • the method preferably comprises the step of using a PROTAC compound to bind KIFC1 and to recruit the E3 ligase to KIFC1, optionally wherein the PROTAC compound is a compound or pharmaceutically acceptable salt thereof as defined according to any aspect or embodiment disclosed herein.
  • a method of degrading KIFC1 in a cell preferably a cancer cell, the method comprising contacting the cell with a compound or pharmaceutically acceptable salt thereof as defined according to any aspect or embodiment thereof disclosed herein, or a pharmaceutical composition as defined herein.
  • said method of degrading KIFC1 may not be a method of treatment practised on the human or animal body.
  • the method is not a method of treatment by therapy.
  • the method is not an in vivo method.
  • such a method may be an in vitro or ex- vivo method.
  • the cancer cell is typically a mammalian cancer cell, preferably a human cancer cell.
  • the method of degrading KIFC1 described above is a method of treatment by therapy
  • the method suitably comprises contacting the cancer cell in a patient (suitably wherein a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof has been administered to the patient).
  • the patient is a patient that has been diagnosed with cancer.
  • the present invention also provides a method of treating a disease or condition mediated by KIFC1 in a cell.
  • the disease or condition may be associated with overexpression of KIFC1 relative to normal, healthy tissue that is not suffering from the disease or condition.
  • the invention provides a compound as described herein, such as defined in the claims, or a pharmaceutically acceptable salt thereof, per se.
  • the compound may for instance be provided in the form of a solid dosage form, e.g. a salt form, such as a metal salt form.
  • a solid dosage form e.g. a salt form, such as a metal salt form.
  • Figure 1 Immunoblots for KIFC1 in cancer cell lines treated with CRBN-KIFC1- PROTACs. MDA-MB-231 and BT549 cells were treated with the indicated concentrations for 24 hours and compared with DMSO-treated cells. ⁇ -actin was used as the loading control.
  • FIG. 1 A-(F) Breast cell lines were treated at the displayed concentrations for 24 hours and immunoblotted for KIFC1 to evaluate the degradation profile in cell lines displaying different degrees of centrosome amplification (MDA-MB-231 and BT549 display high CA; MCF10A display low CA). Western blots and quantification shown for each cell line. MA185 induces robust, concentration dependent, KIFC1 degradation in MDA-MB-231 and BT549 cells.
  • FIG. 1 Whole-cell lysates of the breast non-cancerous cell line MCF-10A and breast cancer lines: MCF-7, BT-549, MDA-MB-231 and MDA-MB- 231GFP-KIFC1r were immunoblotted for KIFC1 and CRBN to confirm expression.
  • FIG. 5 Representative immunofluorescence images of MDA-MB-231 cells after 24 hours of MA185 (1 ⁇ M) or vehicle control (DMSO) treatment. Cells were fixed in methanol and stained for KIFC1 (red), Tubulin (grey), and Dapi (blue).
  • B Quantification of KIFC1 degradation plotted as mean fluorescence intensity ⁇ SEM of 7 fields of view, tested by Mann–Whitney U-test for significance, **p ⁇ 0.01,
  • C GFP- KIFC1r degradation in MDA-MB-231GFP-KIFC1r cells.
  • GFP fluorescence was measured by flow cytometry and data are presented as a percentage of GFP-KIFC1r degradation after 24 hours of MA185 treatment in different concentrations normalised by DMSO control.
  • D GFP-KIFC1r degradation in MDA-MB-231GFP-KIFC1rcells. GFP fluorescence was measured by flow cytometry and data are presented as the percentage of GFP-KIFC1r degradation after MA185 (1 ⁇ M) treatment at different time points.
  • E Immunoblotting of endogenous KIFC1 in MDA-MB-231 cells.
  • FIG. 1 The growth inhibitory activities of MA185 and AZ82 in breast cell lines were analysed by 72 hours CellTiter 96 assay and presented as mean ⁇ SEM of 2 or 3 independent experiments. Absorbance values were normalised by DMSO on the concentration-response curves.
  • Figure 7. (A) Representative images of colony formation assay of breast cell line displaying low centrosome amplification (MCF-10A) and triple-negative breast cancer cells (TNBC) with high levels of centrosome amplification (MDA-MB-231 and BT-549).
  • the cells were treated with MA185 (1 ⁇ M), AZ82 (1 ⁇ M) or vehicle control (DMSO) treatment. Cells were grown from 7 to 12 days, fixed in paraformaldehyde and stained in crystal violet. MA185 significantly reduced the survival of TNBC cells when compared with AZ82 and DMSO treatment.
  • B Quantification of colony formation assay. Colonies were quantified using the colony area plug-in (Image-J software). Colony numbers are shown as percentages normalised with the DMSO control. Bars represent mean ⁇ SEM, tested by two-way ANOVA with Tukey’s post-hoc test for significance, **p ⁇ 0.01, ***p ⁇ 0.001.
  • (C) The cells were treated with MA185 (1 ⁇ M), AZ82 (1 ⁇ M) or vehicle control (DMSO) for 24 hours, fixed in ethanol and stained for propidium iodide to evaluate the DNA content (cell cycle profile) by flow cytometry. Bars are percentage values of 1 experimental replicate. MA185 treatment caused G2 cell cycle arrest in both TNBC lines.
  • the inventors propose that compounds of the invention exhibit their surprising anti- cancer activity by virtue of the compounds comprising a ligand capable of binding KIFC1, where said ligand is covalently bonded to a ligand capable of binding an E3 ligase, preferably CRBN, via a linker group.
  • the inventors postulate that the compounds of the present invention first bind to KIFC1, and then recruit an E3 ligase to mediate ubiquitination/proteasomal degradation of KIFC1.
  • the compounds of the present invention can bind to another KIFC1 molecule.
  • the compounds of the present invention are, therefore, advantageously more effective than known inhibitors of KIFC1 which act merely as antagonists and do not affect expression of KIFC1.
  • General Various embodiments of the compounds of the present invention are described in this application. It should also be understood below that where an embodiment of a compound of any of the formulae described herein is further defined (i.e. by reference to the respective substituent groups), the definition also applies to pharmaceutically acceptable salts of the respective compounds. It is intended that features specified in each of these embodiments may be combined with other features specified in other embodiments to provide further embodiments of the invention. The skilled person will also appreciate that any chemically impossible compounds that would result from combining one of more of the embodiments below are not intended to be encompassed within the context of this invention.
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • substituents typically there will be from 1 to 3 substituents, in embodiments 1 or 2 substituents, such as only 1 substituent.
  • “optionally substituted” means optionally substituted with 1 to 3 substituents selected from halogen, OH, SH, NH2, CN, COOH, CONH, C1-6 alkyl, C1-6 haloalkyl (e.g. trihalomethyl such as trifluoromeethyl), C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl.
  • alkyl Alkyl, Alkenyl and Alkynyl
  • alkylene alkenyl, alkenylene, alkynyl or “alkynylene” are used herein to refer to both straight and branched chain acyclic forms. Cyclic analogues thereof are referred to as cycloalkyl, etc.
  • alkyl includes monovalent, straight or branched, saturated, acyclic hydrocarbyl groups.
  • alkyl is C1-10 alkyl, in another embodiment C1-6 alkyl, in another embodiment C1-4 alkyl, such as methyl, ethyl, n-propyl, i-propyl or t-butyl groups.
  • alkylene includes divalent, straight or branched, saturated, acyclic hydrocarbylene groups.
  • alkylene may be a C1-10 alkylene, a C1-6 alkylene, or a C1-4 alkylene, such as methylene, ethylene, n-propylene, i-propylene or t-butylene groups.
  • alkenyl includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon double bond and, in some embodiments, no carbon-carbon triple bonds. Unless specified otherwise, alkenyl may be a C 2-10 alkenyl, optionally C 2-6 alkenyl, or C 2-4 alkenyl.
  • alkenylene includes divalent, straight or branched, unsaturated, acyclic hydrocarbylene groups having at least one carbon-carbon double bond and, optionally, no carbon-carbon triple bonds.
  • alkenylene may be a C 2-10 alkenylene, a C 2-6 alkenylene, or a C 2-4 alkenylene.
  • alkynyl includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon triple bond and, optionally, no carbon-carbon double bonds.
  • alkynyl may be C 2-10 alkynyl, optionally still C 2-6 alkynyl, further optionally C 2-4 alkynyl.
  • alkynylene includes divalent, straight or branched, unsaturated, acyclic hydrocarbylene groups having at least one carbon-carbon triple bond and, in one embodiment, no carbon-carbon double bonds. Unless otherwise specified, alkynylene may be a C2-10alkynyl, optionally C2-6alkynyl, or C2-4alkynyl.
  • Haloalkyl, Haloalkenyl and Haloalkynyl refers to an alkyl group wherein at least one H is replaced by a halo group. Unless otherwise specified, haloalkyl refers to substitution by from 1-3 halo groups, e.g. 1.
  • haloalkylene refers to an alkylene group wherein at least one H is replaced by a halo group. Unless otherwise specified, haloalkylene refers to substitution by from 1-3 halo groups, e.g. 1. Examples include trihalomethyl, trihaloethyl, e.g. trifluoromethyl, trifluoroethyl, etc.
  • haloalkyenyl refers to an alkenyl group wherein at least one H is replaced by a halo group.
  • haloalkenyl refers to substitution by from 1-3 halo groups, e.g. 1. Examples include trihaloethylene, e.g. trifluoroethylene, etc.
  • haloalkenylene refers to an alkenylene group wherein at least one H is replaced by a halo group.
  • haloalkenylene refers to substitution by from 1-3 halo groups, e.g.1. Examples include trihaloethyl, e.g. trifluoroethylene, etc.
  • haloalkynyl refers to an alkynyl group wherein at least one H is replaced by a halo group.
  • haloalkynyl refers to substitution by from 1-3 halo groups, e.g. 1. Examples include trihalopropynyl, e.g. trifluoropropynyl, etc.
  • haloalkynylene refers to an alkynylene group wherein at least one H is replaced by a halo group. Unless otherwise specified, haloalkynylene refers to substitution by from 1-3 halo groups, e.g.1. Examples include trihalopropynyl, e.g. trifluoropropynyl, etc.
  • heteroalkyl includes alkyl groups in which up to three carbon atoms, optionally up to two carbon atoms, optionally still one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkyl carbon atoms remains.
  • the heteroalkyl group may be C-linked or hetero-linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • heteroalkylene includes alkylene groups in which up to three carbon atoms, optionally up to two carbon atoms, optionally still one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkylene carbon atoms remains.
  • the heteroalkylene group may be C-linked or hetero-linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • heteroalkenyl includes alkenyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, in another embodiment one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkenyl carbon atoms remains.
  • the heteroalkenyl group may be C-linked or hetero- linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • heteroalkenylene includes alkenylene groups in which up to three carbon atoms, optionally up to two carbon atoms, optionally still one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkenyl carbon atoms remains.
  • the heteroalkenylene group may be C-linked or hetero-linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • heteroalkynyl includes alkynyl groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, in another embodiment one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkynyl carbon atoms remains.
  • the heteroalkynyl group may be C-linked or hetero- linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • heteroalkynylene includes alkynylene groups in which up to three carbon atoms, in one embodiment up to two carbon atoms, in another embodiment one carbon atom, are each replaced independently by O, S or N, provided at least one of the alkynyl carbon atoms remains.
  • the heteroalkynylene group may be C-linked or hetero- linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through O, S or N.
  • Carbocyclic and Heterocyclic Groups As used herein, the term “carbocyclic group” (also referred to as carbocyclic ring) means a 3 to 8-membered carbon ring.
  • the carbocyclic group may be saturated or unsaturated.
  • the carbocyclic group may be a cycloalkyl group or an aryl group.
  • the term “heterocyclic group” (also referred to as heterocyclic ring) means a 3 to 8-membered carbon ring comprising at least one heteroatom selected from O, N and S.
  • the heterocyclic group may be saturated or unsaturated.
  • the heterocyclic group may be a heterocycloalkyl group or a heteroaryl group.
  • U may be selected from CH, CH2, O, S, NH and NH2-. Where U is absent, denotes a 5- membered carbocyclic ring or heterocyclic ring.
  • cycloalkyl includes monovalent, saturated, cyclic hydrocarbyl groups. In one embodiment cycloalkyl is C3-10cycloalkyl, in another embodiment C3-6 cycloalkyl such as cyclopentyl and cyclohexyl.
  • heterocycloalkyl includes cycloalkyl groups in which up to three carbon atoms, optionally up to two carbon atoms, optionally still one carbon atom, are each replaced independently by O, S or N, provided at least one of the cycloalkyl carbon atoms remains.
  • heterocycloalkyl groups include oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4- oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4- thieazepanyl and 1,4-diazepanyl.
  • the heterocycloalkyl group may be C-linked or N- linked, i.e. it may be linked to the remainder of the molecule through a carbon atom or through a nitrogen atom.
  • cycloalkenyl includes monovalent, partially unsaturated, cyclic hydrocarbyl groups having at least one carbon-carbon double bond and, in one embodiment, no carbon-carbon triple bonds. Unless specified otherwise, cycloalkenyl may be a C 3-10 cycloalkenyl, or a C 5-10 cycloalkenyl e.g. cyclohexenyl or cyclopentenyl.
  • heterocycloalkenyl means includes cycloalkenyl groups in which up to three carbon atoms, optionally up to two carbon atoms, optionally still one carbon atom, are each replaced independently by O, S or N, provided at least one of the cycloalkenyl carbon atoms remains.
  • heterocycloalkenyl groups include 3,4-dihydro-2H-pyranyl, 5-6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl and 1,2,5,6-tetrahydropyridinyl.
  • the heterocycloalkenyl group may be C-linked or N- linked, i.e.
  • aryl includes monovalent, aromatic, cyclic hydrocarbyl groups, such as phenyl or naphthyl (e.g.1-naphthyl or 2-naphthyl).
  • the aryl groups may be monocyclic or polycyclic fused ring aromatic groups, and are preferably monocyclic aromatic groups.
  • Preferred aryl groups are C 6 aryl.
  • aryl groups are monovalent derivatives of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, coronene, fluoranthene, fluorene, as-indacene, s-indacene, indene, naphthalene, ovalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene and rubicene.
  • Aryl may include “arylalkyl” meaning alkyl substituted with an aryl group, e.g. benzyl.
  • heteroaryl includes aryl groups in which one or more carbon atoms are each replaced by heteroatoms independently selected from O, S, N and NR N , where R N is defined below (and in one embodiment is H or alkyl (e.g. C1-6alkyl)).
  • R N is defined below (and in one embodiment is H or alkyl (e.g. C1-6alkyl)).
  • the heteroaryl groups may be monocyclic or polycyclic (e.g. bicyclic) fused ring heteroaromatic groups.
  • heteroaryl groups contain 5-14 ring members (preferably 5-10 members) wherein 1, 2, 3 or 4 ring members are independently selected from O, S, N and NR N .
  • a heteroaryl group may be 5, 6, 9 or 10 membered, e.g.5-membered monocyclic, 6-membered monocyclic, 9-membered fused-ring bicyclic or 10-membered fused-ring bicyclic.
  • the heteroaryl group is an optionally substituted polycyclic (e.g. bicyclic) fused ring heteroaromatic group (e.g. benzodiazepines).
  • Monocyclic heteroaromatic groups include heteroaromatic groups containing 5-6 ring members wherein 1, 2, 3 or 4 ring members are independently selected from O, S, N or NR N .
  • Examples of 5-membered monocyclic heteroaryl groups are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,3 oxadiazolyl, 1,2,4 oxadiazolyl, 1,2,5 oxadiazolyl, 1,3,4 oxadiazolyl, 1,3,4 thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5 triazinyl, 1,2,4 triazinyl, 1,2,3 triazinyl and tetrazolyl.
  • 6-membered monocyclic heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.
  • Bicyclic heteroaromatic groups include fused-ring heteroaromatic groups containing 9- 14 ring members wherein 1, 2, 3, 4 or more ring members are independently selected from O, S, N or NR N .
  • 9-membered fused-ring bicyclic heteroaryl groups are benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3- c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolininyl, imidazo[1,2-a]pyrazo
  • 10-membered fused-ring bicyclic heteroaryl groups are quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7- naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4- d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,
  • heteroatom containing groups such as heteroalkyl etc.
  • a numerical of carbon atoms is given, for instance C3-6heteroalkyl
  • a C3-6heteroalkyl group will contain less than 3-6 chain carbon atoms.
  • R N is H, alkyl, cycloalkyl, aryl, heteroaryl, -C(O)-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -S(O)t-alkyl, –S(O)t-aryl or – S(O)t-heteroaryl.
  • R N may, in particular, be H, alkyl (e.g. C1-6alkyl) or cycloalkyl (e.g. C3- 6cycloalkyl).
  • t is independently 0, 1 or 2, for example 2. Typically, t is 0.
  • a group has at least 2 positions which may be substituted, the group may be substituted by both ends of an alkylene or heteroalkylene chain to form a cyclic moiety.
  • carbon chain means a path of uninterrupted carbon atoms. The carbon chain may be saturated or unsaturated.
  • Compounds of the present invention The present invention provides compounds according to Formula (I), L 1 -R-L 2 , wherein L 1 , R, and L 2 are as defined in any of the aspects and embodiments described herein.
  • the term “ligand capable of binding” means a ligand that can bind to a target protein, and may have agonist or antagonist effect on the target protein.
  • the ligand may be an allosteric ligand.
  • the ligand may bind to the active-site of the target protein.
  • a target protein may be bind to the active-site of the target protein.
  • One such method includes the example equilibrium dissociation constant (K D ).
  • K D equilibrium dissociation constant
  • Other methods may include, for instance, the use of fluorescently tagged ligands and target proteins to effect fluorescence resonance energy transfer (FRET).
  • FRET fluorescence resonance energy transfer
  • L1 is a ligand capable of binding kinesin family member C1 (KIFC1).
  • L2 is a ligand capable of binding E3 ligase.
  • the ligand capable of binding kinesin family member C1 (KIFC1), L1 may be selected from AZ82 (CAS 1449578-65-7), CW069 (CAS 1594094-64-0) and SR31527 (Zhang et al; doi: 10.1042/BJ20150992), and derivatives thereof.
  • L 1 or L 2 is defined with reference a named compound (or drug)
  • a monovalent derivative of said named compound is intended, wherein at least one H is removed to provide a radical, where said radical forms a covalent bond with the linker group R.
  • the radical is provided at a position which does not interfere with the binding activity of the ligand.
  • the binding interactions of ligands with their target proteins may be resolved through various methods, for example via X-ray crystallography, or in silico computer modelling. For instance, where L 1 is defined with reference to AZ82, a radical of AZ82 is contemplated which forms a covalent bond with linker group R.
  • L 1 may be a derivative of AZ82, SW069 or SR31527.
  • a coupling moiety is provided to provide a covalent bond between the derivative of AZ82, CW069, SR31527 and the linker group R.
  • a H atom may be removed (e.g. a H on an aryl group) and substituted with OH, CH 2 OH, COOH, CONH, CH 2 COOH, or CH 2 CONH to provide an alternative coupling moiety.
  • the coupling moiety is suitable for a peptide coupling e.g. COOH or CONH.
  • Preferred positions for modification of AZ82 for attachment to the linker group R include the pyrolidine group.
  • the pyrolidine group may provide a pyrolidinyl group for instance.
  • L 1 may be a derivative of AZ82, that is to say a modified version of AZ82.
  • L 1 may be a derivative of AZ82 (AZ82-D1) having the following formula, wherein the pyrolidine group has been removed to provide an amide radical.
  • Preferred positions of CW069 for a covalent bond to the linker group R include the phenylmethylene groups.
  • E3 ligase (also referred to ubiquitin ligase) is a protein which mediates ubiquitination of a target protein substrate, and thus mediates degradation of said target protein substrate. E3 ligase may form a complex with an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the target protein substrate.
  • E3 ligase thus mediates ubiquitination of, and degradation of, KIFC1.
  • the E3 ligase may be an E3 ligase complex comprising the protein cereblon (CRBN).
  • CRBN is a 442-amino acid protein that forms a Cullin-4-RING E3 ubiquitin ligase (CRL4) complex (Chamberlain et al; DOI: doi:10.1038/nsmb.2874).
  • CRBN ligands therefore recruit the E3 ligase complex to the target protein substrate.
  • the ligand capable of binding the E3 ligase, L 2 may therefore be a ligand capable of binding cereblon (CRBN).
  • L 2 may therefore be thalidomide, pomalidomide, or lenalidomide, or a derivative thereof.
  • L 2 is pomalidomide, or a derivative thereof.
  • L2 may be pomalidomide, wherein the aniline group provides an amine radical to form a covalent bond with R as shown in the following formula:
  • L 2 may be lenalidomide, wherein the aniline group provides an amine radical to form a covalent bond with R as shown in the following formula:
  • L2 may alternatively be a derivative of thalidomide, pomalidomide or thalidomide.
  • a coupling moiety is provided to provide a covalent bond between thalidomide, pomalidomide or lenalidomide with the linker group R.
  • the amino group of the aniline in lenalidomide or pomalidomide may be removed and substituted for OH, CH2, CH2OH, COOH, CONH, CH2COOH, CH2CONH to provide an alternative coupling moiety.
  • a H atom of the aryl group in thalidomide may be removed and substituted with OH, CH2, CH2OH, COOH, CONH, CH2COOH, or CH2CONH to provide an alternative coupling moiety.
  • the coupling moiety is suitable for a peptide coupling e.g. OH, NH2, COOH or CONH or CH2COOH or CH2CONH.
  • L2 may be a derivative of thalidomide, that is to say a modified version of thalidomide (Th).
  • L2 may be a derivative of thalidomide (Th-D1) having the following formula, wherein a methylene group has been introduced to provide a carbon radical to forma covalent bond with R as shown in the following formula.
  • the ligand capable of binding KIFC1 and the ligand capable of binding an E3 ligase are covalently linked via a linker group.
  • the linker may have a chain length having an integer value (i.e. whole number) of from 3 to 20.
  • the chain length of the linker group may have an integer value of from 3 to 12, and is counted as the number of adjacent atoms along the shortest possible path between L1 and L2.
  • the atoms provided in the chain length of the linker group may comprise atoms of a carbocyclic or heterocyclic group. That is to say, atoms comprised in the carbocyclic or heterocyclic group may be integrally formed with the linker group R. For instance, the following examples all have linker group chain length of 6.
  • the linker group R is covalently bonded to the ligand capable of binding to an E3 ligase at one end (i.e.
  • the covalent bond between R and L1 is a peptide bond (i.e. CONH).
  • the covalent bond between R and L1 is a heteroalkyl bond (e.g. CH2O, CH2NH).
  • the covalent bond between R and L2 is a peptide bond (i.e. CONH).
  • the covalent bond between R and L2 is a heteroalkyl bond (e.g. CH2O, CH2NH).
  • the covalent bond between R and L1, and the covalent bond between R and L2 are each independently peptide bonds (i.e. CONH).
  • the covalent bond between R and L1, and the covalent bond between R and L2 are each independently heteroalkyl bonds (e.g. CH2O, CH2NH).
  • the covalent bond between R and L 1 is a peptide bond
  • the covalent bond between R and L 2 is a heteroalkyl bond (e.g.
  • R may be a linker group with a chain length having an integer of from 3 to 20 atoms.
  • R is a linker group with a chain length having an integer of from 3 to 12 atoms, optionally 4 to 11 atoms, preferably 5 to 10 atoms, preferably still 6 to 9 atoms.
  • R is a linker group with a chain length having an integer of 5 to 7 atoms (e.g.6 atoms).
  • the atoms comprised in the chain length may be selected from C, O and NH.
  • the chain length consists of carbon atoms, that is to say the linker group is a carbon chain.
  • R has the formula (CH2)n, wherein n is an integer selected from 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 preferably from 4, 5, 6, 7, 8, 9, and 10; and preferably still from 4, 5, 6, 7 and 8 (e.g.6).
  • the compounds of the present invention may have a following formula according to any one of formulas (A’)-(D’), or a pharmaceutically acceptable salt thereof Formula (A’) Formula (B’) Formula (C’) Formula (D’) Pharmaceutically Acceptable Salts
  • pharmaceutically acceptable salt includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids and bases.
  • Compounds of the invention that contain basic, e.g. amino, groups are capable of forming pharmaceutically acceptable salts with acids.
  • pharmaceutically acceptable acid addition salts of the compounds of the invention include, but are not limited to, those of inorganic acids such as hydrohalic acids (e.g.
  • pharmaceutically acceptable acid addition salts of the compounds of the invention include, but are not limited to, those of organic acids such as aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which include: aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid or butyric acid; aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid; dicarboxylic acids such as maleic acid or succinic acid; aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, phenylacetic acid, diphenylacetic acid or triphenylacetic acid; aromatic hydroxyl acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-car
  • acid addition salts of the compounds of the invention include, but are not limited to, those of glycolic acid, glucuronic acid, furoic acid, glutamic acid, anthranilic acid, salicylic acid, mandelic acid, embonic (pamoic) acid, pantothenic acid, stearic acid, sulfanilic acid, algenic acid and galacturonic acid.
  • the compound of the invention comprises a plurality of basic groups, multiple centres may be protonated to provide multiple salts, e.g. di- or tri-salts of compounds of the invention.
  • a hydrohalic acid salt of a compound of the invention as described herein may be a monohydrohalide, dihydrohalide or trihydrohalide, etc.
  • the salts include, but are not limited to those resulting from addition of any of the acids disclosed above.
  • two basic groups form acid addition salts.
  • the two addition salt counterions are the same species, e.g. dihydrochloride, dihydrosulphide etc.
  • the pharmaceutically acceptable salt is may be a hydrochloride salt, such as a dihydrochloride salt.
  • pharmaceutically acceptable basic salts of the compounds of the invention include, but are not limited to, metal salts such as alkali metal or alkaline earth metal salts (e.g. sodium, potassium, magnesium or calcium salts) and zinc or aluminium salts.
  • pharmaceutically acceptable basic salts of the compounds of the invention include, but are not limited to, salts formed with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines (e.g. diethanolamine), benzylamines, N-methyl-glucamine, amino acids (e.g. lysine) or pyridine.
  • the pharmaceutically acceptable salt thereof is a base addition salt, such as a metal salt (e.g. a sodium salt), or a salt formed using ammonia, a pharmaceutically acceptable organic amine or a heterocyclic base.
  • a metal salt e.g. a sodium salt
  • a salt formed using ammonia e.g. a pharmaceutically acceptable organic amine or a heterocyclic base.
  • Pharmaceutically acceptable derivatives Compounds according to any aspect or embodiment disclosed herein, or pharmaceutically acceptable salts thereof, may be provided as pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivative herein includes any pharmaceutically acceptable solvate (e.g. hydrate) or prodrug.
  • Prodrugs The invention includes prodrugs of the compounds of the invention.
  • Prodrugs are derivatives of compounds of the invention (which may have little or no pharmacological activity themselves), which can, when administered in vivo, be converted into compounds of the invention.
  • Prodrugs can, for example, be produced by replacing functionalities present in the compounds of the invention with appropriate moieties which are metabolized in vivo to form a compound of the invention.
  • prodrugs are well-known in the art, as discussed in Bundgaard, Design of Prodrugs 1985 (Elsevier), The Practice of Medicinal Chemistry 2003, 2 nd Ed, 561-585 and Leinweber, Drug Metab. Res.1987, 18: 379.
  • Amorphous & crystalline forms The compounds of the invention may exist in solid states from amorphous through to crystalline forms. All such solid forms are included within the invention, including solvated (e.g. hydrated) and non-solvated forms, as described below. Solvates & hydrates The compounds of the invention may exist in both unsolvated and solvated solid forms.
  • solvate includes molecular complexes comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules such as water or C 1-6 alcohols, e.g. ethanol.
  • solvent molecules such as water or C 1-6 alcohols, e.g. ethanol.
  • hydrate means a “solvate” where the solvent is water.
  • Isomeric forms Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto- and enol-forms. All such isomeric forms are included within the invention.
  • the isomeric forms may be in isomerically pure or enriched form, as well as in mixtures of isomers (e.g. racemic or diastereomeric mixtures). Accordingly, the invention provides, for use in the methods and treatments described herein: ⁇ stereoisomeric mixtures of compounds of the invention; ⁇ a diastereomerically enriched or diastereomerically pure isomer of a compound of the invention; or ⁇ an enantiomerically enriched or enantiomerically pure isomer of a compound of the invention. Where appropriate, isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques - such as chiral chromatography - , resolution techniques and recrystallization techniques).
  • isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
  • Isotopic labelling The invention includes pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Certain isotopically-labelled compounds of the invention for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes 3 H and 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed. Treatment The compounds of the present invention have advantageously been found to be useful as a medicament, more particularly for use in the treatment of cancer. Whilst an individual enantiomer is proposed for the uses, methods and treatments disclosed herein, those skilled in the art will understand that mixtures of isomers, e.g. racemic mixtures may also be provided.
  • treatment includes curative and prophylactic treatment.
  • a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment.
  • the amount of the compound of the invention administered should be a therapeutically effective amount where the compound or derivative is used for the treatment of a disease or condition and a prophylactically effective amount where the compound or derivative is used for the prevention of a disease or condition.
  • terapéuticaally effective amount refers to the amount of compound needed to treat or ameliorate a targeted disease or condition.
  • prophylactically effective amount used herein refers to the amount of compound needed to prevent a targeted disease or condition.
  • the exact dosage will generally be dependent on the patient’s status at the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time, frequency and route of administration, drug combinations, reaction sensitivities and the patient’s tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician.
  • An effective dose may in instances be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 1000 mg/kg/day, e.g. 1 mg/kg/day to 100 mg/kg/day.
  • Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • Administration & Formulation For pharmaceutical use, the compounds of the invention may be administered as a medicament by enteral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), oral, intranasal, rectal, vaginal, urethral and topical (including buccal and sublingual) administration.
  • the compounds of the invention should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • the compounds of the invention may be administered as crystalline or amorphous products.
  • the compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient includes any ingredient other than the compound(s) of the invention which may impart either a functional (e.g. drug release rate controlling) and/or a non-functional (e.g.
  • Typical pharmaceutically acceptable excipients include: ⁇ diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; ⁇ lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; ⁇ binders, e.g.
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention, e.g.
  • Oral administration The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano- particulates, liquids (e.g.
  • Formulations suitable for oral administration may also be designed to deliver the compounds the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
  • Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
  • rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
  • rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
  • Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs.
  • Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986.
  • the formulation of tablets is discussed in H. Lieberman and L.
  • the compounds of the invention can be administered parenterally.
  • the compounds of the invention may be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ.
  • Suitable means for administration include intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous or oily solutions.
  • excipients such as sugars (including but not restricted to glucose, mannitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water (WFI).
  • WFI sterile, pyrogen-free water
  • Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e. polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides.
  • formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
  • preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
  • the compounds of the invention can be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane, or as nasal drops.
  • a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(lactic-co-glycolic acid) (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Transdermal administration Suitable formulations for transdermal application include a therapeutically effective amount of a compound of the invention with carrier.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Combination Therapy The compounds of the invention may be administered alone or may be administered in combination with another compound of the invention or another therapeutic agent (i.e. a different agent to the compound of the invention). Preferably, the compound of the invention and the other therapeutic agent are administered in a therapeutically effective amount.
  • the compound of the present invention may be administered either simultaneously with, or before or after, the other therapeutic agent.
  • the compounds of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
  • the invention provides a product comprising a compound of the invention and another therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of cancer.
  • the therapy is the treatment of a disease or condition mediated by KIFC1.
  • Products provided as a combined preparation include a composition comprising the compound of the invention and the other therapeutic agent together in the same pharmaceutical composition, or the compound of the invention and the other therapeutic agent in separate form, e.g. in the form of a kit.
  • the invention thus provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above in “Administration and formulation”.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention may typically comprise directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g.
  • L1 is a ligand capable of binding kinesin family member C1 (KIFC1)
  • L2 is a ligand capable of binding E3 ligase
  • R is a linker group with a chain length having an integer of at least 3 atoms.
  • R is a linker group with a chain length having an integer of from 3 to 20 atoms, optionally from 3 to 12, optionally still from 4 to 8 atoms, further optionally from 5 to 7 atoms (e.g.6 atoms).
  • R is selected from optionally substituted C3-C12 alkylene, optionally substituted C3-C12 haloalkylene, optionally substituted C3-C12 heteroalkylene, optionally substituted C3-C12 alkenylene, optionally substituted C3-C12 haloalkenylene, optionally substituted C3-C12 heteroalkenylene; optionally substituted C3-C12 alkynylene; optionally substituted C3-C12 haloalkynylene and optionally substituted C3-C12 heteroalkynylene; or wherein at least 1 atom of the chain length forms part of an optionally substituted carbocyclic or optionally substituted heterocyclic group; optionally wherein the optionally substituted carbocyclic or optionally substituted heterocyclic group is selected from optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 5 -C 8 cycloalkenyl, optionally substituted C 3
  • R is a carbon chain, optionally a C3-C12 carbon chain, optionally still a C4-C8 carbon chain, further optionally a C5-C7 carbon chain (e.g. a C6 carbon chain). 6.
  • the carbon chain is alkylene or alkenylene. 7.
  • R is R’(CH2)nR’’ and the compound is according to formula (II) or a pharmaceutically acceptable salt thereof:
  • Formula (II) wherein: R’ and R’’ are each independently selected from CH2, O, S, NH, CO, COO and CONH and n is an integer from 1 to 10; or R’ and R’’ are each independently absent and n is an integer of from 3 to 12.
  • R’ and R’’ are each independently selected from CH 2 , O, S, NH, CO, COO and CONH; and n is from 1 to 9, optionally wherein n is an integer from 2 to 8, optionally still from 3 to 7 (e.g.
  • n 4, 5 or 6); or wherein R’ and R’’ are each independently absent and n is an integer from 3 to 11, optionally from 4 to 10, optionally still from 5 to 9, further optionally from 6 to 8. 9. A compound according to clause 8, wherein R’ and R’’ are each independently absent and n is an integer that is 6 or 7, preferably 6. 10.
  • L 1 is according to formula (III): Formula (III) wherein W and V are each independently selected from O, S, NH, CO, COO and CONH; R 1 and R 2 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkenyl, C 1 -C 6 heteroalkenyl, C 1 - C 6 alkynyl, C 1 -C 6 haloalkynyl, C 1 -C 6 heteroalkynyl, -ONHR 6 and -OR 6 ; R 3 , R 4 and R 5 are each independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alken
  • L 1 is according to formula (IV): Formula (IV) wherein Z is selected from O, NH and S; X is CH and Y is N, or X is N and Y is CH; and R1-R5, W and V are as defined in clause 10.
  • L1 is according to formula (V): ; Formula (V) wherein R1 and R2 are each independently C1-C6 alkyl; and R4 is C1-C6 haloalkoxy.
  • L1 is selected from AZ82, CW069, SR31527, or derivatives thereof CW069 SR31527.
  • L2 is a ligand capable of binding CRBN, optionally wherein the ligand capable of binding CRBN is selected from thalidomide, pomalidomide, or lenalidomide, or a derivative thereof; preferably wherein the CRBN ligand is pomalidomide or a derivative thereof.
  • L2 is according to formula (VIIb): Formula (VIIb) wherein a 6-membered carbocyclic or heterocyclic group when U’ is CH or CH2, or is a 5-membered carbocyclic or heterocyclic group when U’ is absent; X’ and Y’ are each independently CH2, CO or absent; Z’ is CH2 or absent; W’ is NH, CH2, COOH, CONH or O; and R 7 is optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 3 -C 6 heterocycloalkyl, optionally substituted C 3 -C 6 cycloalkenyl or optionally substituted C 3 - C 6 heterocycloalkenyl, optionally wherein R 7 is optionally substituted C 3 -C 6 heterocycloalkyl selected from pyrolidinyl, piperidinyl, and cyclic imidyl, optionally still wherein R 7 is a cyclic imidyl, optionally still wherein R 7 is
  • a pharmaceutical composition comprising a compound according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 23.
  • 24. A compound according to any one of clauses 1 to 21, or a pharmaceutical composition according to clause 22, for use in the treatment of cancer.
  • 25. A compound according to clause 24 wherein the cancer is a solid tumour, optionally wherein the solid tumour is selected from melanoma, glioblastoma, pancreatic cancer, and breast cancer, optionally: (i) wherein the cancer is breast cancer, wherein the breast cancer is triple negative breast cancer (TNBC); or (ii) wherein the cancer melanoma, wherein the melanoma is uveal melanoma.
  • TNBC triple negative breast cancer
  • the carboxylic acid (0.20 mmol, 1.0 eq.) was then added to the solution, followed by hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (0.22 mmol, 1.1 eq.) and N,N-diisopropylethylamine (DIPEA) (0.80 mmol, 4.0 eq,).
  • HATU hexafluorophosphate azabenzotriazole tetramethyl uronium
  • DIPEA N,N-diisopropylethylamine
  • BT-549 cells were cultured in RPMI media supplemented with 10% foetal bovine serum (FBS), 1% penicillin/streptomycin (P/S), and 1 ⁇ g/mL of insulin.
  • FBS foetal bovine serum
  • P/S penicillin/streptomycin
  • MDA- MB-231 and Hela cells were cultured in DMEM media supplemented with 10% FBS and 1% of P/S, and MCF-7 cells were kept in the same medium with the addition of 10 ⁇ g/mL of insulin.
  • MCF-10A cells were cultured in DMEM/F-12: 5% horse serum, 20 ng/mL EGF, 100 ng/mL Cholera toxin + 500ng/mL Hydrocortisone and 10 ⁇ g/mL of insulin.
  • MDA-MB-231GFP-KIFC1 cells were generated by transducing the parental MDA-MB-231 cells with lentiviral particles to generate stable cells expressing doxycycline-inducible GFP-KIFC1 constructs, where the KIFC1 sequence has been modified to make it resistant to a well-characterised KIFC1 siRNA. Polyclonal populations were selected by adding puromycin (1 ⁇ g/mL) to the culture media. All cells were grown in a humidified atmosphere containing 5% CO2 at 37 °C.
  • Protein concentrations in the samples were determined using a Pierce BCA Protein Assay Kit (Thermo Fisher Scientific) following the manufacturer’s protocol, and absorbance at 562 nm was determined by Perkin Elmer Wallac 1420 Victor2 microplate reader.20 ⁇ g of total protein were mixed with 6 ⁇ sample buffer (1 M DTT, 1% bromophenol blue) and heated at 100 °C for five minutes before loading and running them on SDS-PAGE (10% gel). Proteins were transferred from the gel to a nitrocellulose membrane using Trans-Blot Turbo RTA Transfer Kit (BioRad) on a Trans-Blot Turbo (transfer system) (BioRad).
  • Blocking and incubations were performed in Tris-buffered saline with 0.1% w/v Tween-20 (TBST) with 5% w/v low-fat milk and 5% w/v BSA for phosphoantibodies. Blocking and secondary antibody incubations were performed for 1 hour at room temperature, and primary antibody incubations at 4 °C overnight. Signals were quantified using fluorophore-conjugated secondary antibodies (IRDye® 800CW Donkey anti-Mouse IgG (LI-COR) 1:10,000; IRDye® 680RD Donkey anti-Rabbit IgG (LI-COR) 1:10,000), scanned on an Odyssey® Imaging System (LI-COR Biosciences).
  • Primary antibodies for immunoblot were as follows: KIFC1 rabbit mAb (1:5000; Abcam), ⁇ -actin rabbit mAb (Cell Signaling Technology, 1:10,000), GAPDH rabbit mAb (1:5000; abcam), Tubulin mouse mAb (1:5000; abcam), CDK1 mouse mAb (1:1000; Cell Signaling Technology), pCDK1(Y15) rabbit mAb (1:1000; Cell Signaling Technology) and PLK1 mouse mAb (1:1000; abcam).
  • Immunofluorescence Cells were seeded at 1 ⁇ 10 5 onto a glass coverslip and cultured overnight in a complete medium.
  • cells were treated with 300 nM or 1 ⁇ M of MA185 or 1 ⁇ M AZ82 and DMSO as a vehicle control 0.1% (v/v) for 24 hours. Then, cells were washed with PBS, fixed, and permeabilised in ice-cold 100% methanol for 20 minutes ( ⁇ 20 °C), followed by blocking with 5% of goat serum in PBS at room temperature for 30 minutes. After blocking, coverslips were incubated with the primary antibodies (1:1000 dilution) in 5% of goat serum in PBS for 2 hours at room temperature in a humidified chamber. Next, coverslips were washed three times for five minutes with PBS before incubation with secondary antibodies diluted in 5% of goat serum in PBS for 1 hour.
  • Coverslips were mounted with mounting medium (mowiol 4- 88 plus DAPI (1 ⁇ g/mL) to stain nuclei).
  • Primary antibodies used for immunofluorescence were as follows: KIFC1 rabbit mAb (Abcam), Pericentrin rabbit mAb (Abcam) and Tubulin rat mAb (Millipore). Secondary antibodies used: Alexa Fluor 488 anti-mouse (Invitrogen), Alexa Fluor 555 anti-rabbit (Invitrogen) and Alexa Fluor 647 anti-rat (Invitrogen).
  • Microscopy & Image Analysis All images were acquired on a Zeiss-LSM880-Airyscan confocal microscope, and ZEN 2.3.sp1 software was used to image the immunofluorescence of stained cells on slides, using 20 ⁇ objective dry lenses (Plan- Apochromat 20x/0.8 M27), taking 2 ⁇ 2 tiled images and five fields of view for each well. Images were analysed in FIJI software version 2.3.0. Mitotic cells were identified using the merged images and marked as regions of interest (ROI). The ROIs were saved as an overlay to further identify mitotic phenotypes. All images were quantitatively analysed by ImageJ/FIJI tool to measure the mean fluorescence intensity.
  • the DAPI channel was used to make ROIs for each nucleus and quantify the KIFC1 signal in each area.
  • Statistical analysis The statistical analyses were performed using GraphPad Prism software version 8.4. The number of biological repeats for all experiments is indicated in figure legends. Data were represented as means ⁇ standard error of the mean (SEM). For comparison between two data sets, a two-tailed unpaired Mann–Whitney U test was used. For analysis of three or more sets of data, the ANOVA test followed by an appropriate post-hoc test of multiple comparisons was used; p ⁇ 0.05 was considered to indicate statistical significance.
  • Example 1 – Synthesis of KIFC1 ligand 9 5-Bromo-2-(3-(trifluoromethoxy)phenyl)pyridine 3 was obtained from a Suzuki coupling between 1 and 2.
  • Sodium carbonate (1.06g, 5.16 mmol, 1.5 eq.)
  • tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.30 mmol, 0.1 eq.)
  • 2,5- dibromopyridine 1 800 mg, 3.36 mmol, 1.0 eq.
  • 3-(trifluoromethoxy)phenylboronic acid 2 (692mg, 3.36 mmol, 1.0 eq.)
  • water 1.2 mL
  • dioxane 8mL
  • Example 3 – Degradation of KIFC1 in vitro We evaluated the efficacy of MA182 and MA185 in degrading KIFC1 in human cell lines.
  • MA185, a CRBN-based PROTAC was effective in promoting KIFC1 degradation after 24 hours of treatment in both MDA-MB-231 and BT549 triple-negative breast cancer cells ( Figure 1).
  • MA185 reduced the KIFC1 levels in a concentration-dependent manner, showing significant degradation of KIFC1 at treatment concentrations of 300nM and above in MDA-MB-231 cells ( Figure 1, quantified in Figure 2).
  • MDA-MB-231 cells were treated with 1 ⁇ M MA185 which led to a significant reduction in KIFC1 expression (Figure 3A) that was determined to be an approximate ⁇ 40% reduction compared to DMSO ( Figure 3B).
  • MA185 was shown to be effective in inducing KIFC1 degradation in cancer cells in a dose dependent manner, more particularly cancer cells associated with high levels of centrosome amplification such as MDA-MB-231 ( Figure 4A-B) and BT-549 cells ( Figure 4 C-D).
  • MA185 PROTAC was less efficient in inducing degradation in a non-cancerous control cell line, MCF-10A ( Figure 4E-F).
  • CRBN non-cancerous control cell line
  • the protein expression levels of KIFC1 and CRBN was evaluated by immunoblotting (Figure 4G).
  • KIFC1 Increased KIFC1 expression was observed in all the cancer cell lines compared to the MCF-10A normal cells. The expression of CRBN was observed in all cell lines.
  • Example 4 – KIFC1 Degradation kinetics We observed partial degradation of endogenous KIFC1 in immunofluorescence staining of KIFC1 in MDA-MB-231 cells ( Figure 5A-B) after 24 hours of treatment with 1 ⁇ M of MA185. To further evaluate the degradation of KIFC1 using MA185, a green fluorescent protein (GFP) model was used.
  • GFP green fluorescent protein
  • MA185 induces KIFC1 degradation by forming a ternary KIFC1: MA185: CRBN complex
  • MA185: CRBN complex we treated cells with KIFC1 inhibitor AZ82 and CRBN inhibitor pomalidomide. These inhibitors were used to compete with MA185 to impair the formation of the ternary complex. Neither AZ82 nor the pomalidomide affected KIFC1 levels ( Figure 5E-F).
  • the combination of MA185 and AZ82 partially prevented KIFC1 degradation, and the combination of MA185 with pomalidomide completely abrogated the degradation effects of the PROTAC by competition.
  • Cells were seeded in 96 well plates, and plating densities were adjusted according to each cell line: BT-549 (7000 cells/well), MDA-MB-231, MDA-MB- 231GFP-KIFC1r, MCF-7 and MCF-10A (2000 cells/well). After overnight culture in a complete medium, cells were treated with serially diluted compounds, MA185 or AZ82 and DMSO as a vehicle control 0.1% (v/v) for 72 hours. Cell viability was determined by using the CellTiter 96® AQueous One Solution Cell Proliferation Assay (Promega), following the manufacturer’s recommendation. Absorbance values were normalised by DMSO-treated cells, and data points were fit in a dose-response curve.
  • IC50 values were calculated using a nonlinear regression analysis of the mean ⁇ SEM from at least six replicates for each biological assay. These data show ( Figure 6F) that MA185 has an IC 50 ( ⁇ M) of 0.12, 0.33 and 0.39 in reducing cell viability of cancerous cell lines MDA-MB-231, BT-549 and MCF-7 respectively. In contrast, KIFC1 inhibitor AZ82 has IC50 values of 8.7, 11.9 and 7.2 in cancerous cell lines MDA-MB-231, BT-549 and MCF-7 respectively.
  • MA185 showed potent inhibitory effects on growth of all the cancer cell lines tested ( Figure 6A-D, quantified in F) and, surprisingly, was significantly more effective in reducing cell viability than its parental inhibitor AZ82.
  • MA185 was determined to be from 36 and 73-fold more potent than KIFC1 inhibitor AZ82 in BT549 and MDA-MB-231 cells, respectively ( Figure 6A, C).
  • Figure 6F shows that MA185 has an IC50 ( ⁇ M) of 0.12, 0.33 and 0.39 in reducing cell viability of cancerous cell lines MDA-MB-231, BT-549 and MCF-7 respectively. In non-cancerous cells MCF-10A, the IC50 is 10.6, revealing that MA185 has significant selectivity for cancer cells.
  • Example 6 Colony Formation Assay The effect of MA185 and AZ82 in colony formation assays of MDA-MB-231, BT-549 and MCF-10A after 24 hours of treatment was investigated.
  • Cells were first seeded at the density of 25.000 cells/well and incubated overnight in a complete medium, followed by treatment with 1 ⁇ M of MA185 or KIFC1 inhibitor AZ82 and DMSO as a vehicle control 0.1% (v/v) for 24 hours.
  • the surviving fraction of cells were counted and re-seeded at low density (1000-2000 cells/well) in a 6-well plate and cultured in a drug- free medium for an additional 7 to 12 days.
  • Cells were plated in a 12-well plate at a density of 1 ⁇ 10 5 cells/well and cultured overnight in a complete medium. After incubation, cells were treated with 1 ⁇ M of MA185 or AZ82 and DMSO as a vehicle control 0.1% (v/v) for 24 hours. Cells were collected after treatment, washed twice in PBS and fixed in 70% ethanol for 2 hours at –20 °C. The fixed cells were rinsed with PBS and incubated with FxCycleTM PI/RNase Staining Solution (Invitrogen) for 30 minutes at room temperature. Single-cell events were gated and analysed by the flow cytometer Cytoflex (Beckman Coulter).
  • KIFC1 is known to bind and be phosphorylated by PLK1 and CDK1, two proteins vital to cell growth, that are often dysregulated in cancer.
  • the effect of MA185 on expression of these interactors was investigated.
  • Figure 7E shows robust downregulation of PLK1 and CDK1/pCDK1 levels after treatment of cancer cells MDA- MB-231 with MA185 in a dose dependent manner. Without wishing to be bound by theory, it is thought that downregulation of this entire protein complex may explain the potent and specific effects on cancer cell growth and the significant improvement in MA185 performance compared to the KIFC1 inhibitor.
  • the compounds of the present invention advantageously exhibit surprisingly high specificity and potency in cancer cells, more particularly in targeting KIFC1 for degradation in cancer cells in vitro.
  • the compounds of the present invention have been surprisingly found to be up to 75 times more potent in inhibiting proliferation of cancer cells, as compared to a control KIFC1 inhibitor (AZ82).
  • the compounds of the present invention have been surprisingly found to be cytotoxic in cancer cells specifically, but do not effect proliferation and survival of normal cells.
  • compounds of the present invention have an IC50 up to 90 times lower in cancer cells, compared to non-cancerous cells.
  • the surprising and unexpected high potency and cancer-specificity of the compounds of the present invention means the compounds of the present invention are particularly suitable for use in the treatment of cancer.
  • the compounds of the present invention also provide an attractive means of reducing expression of KIFC1 in cells as an alternative to other methods such as protein knockdown methods and small molecule inhibitors.
  • the compounds of the present invention may further be advantageously used as a research tool for investigating the role of KIFC1 in cells, particularly cancer cells.

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Abstract

L'invention concerne un ou des composés de formule (I), L1-R-L2 ; dans laquelle L1 est un ligand capable de se lier à l'élément de la famille de la kinésine C1 (KIFC1) tel que défini dans la description, R est un groupe de liaison ayant une longueur de chaîne ayant un nombre entier d'au moins 3 atomes ; et L2 est un ligand capable de se lier à E3 ligase. L'invention concerne également des compositions pharmaceutiques comprenant ledit ou lesdits composés et lesdits composés destinés à être utilisés en tant que médicament, en particulier, pour une utilisation dans le traitement du cancer.
PCT/GB2023/052922 2022-11-11 2023-11-09 Composés chimères ciblant la protéolyse WO2024100402A1 (fr)

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Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"The Practice of Medicinal Chemistry", 2003, pages: 561 - 585
BIN YANG ET AL: "Discovery of Potent KIFC1 Inhibitors Using a Method of Integrated High-Throughput Synthesis and Screening", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 23, 1 January 2014 (2014-01-01), US, pages 9958 - 9970, XP055490564, ISSN: 0022-2623, DOI: 10.1021/jm501179r *
BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
CAS , no. 1594094-64-0
CYRUS K ET AL: "Impact of linker length on the activity of PROTACs", MOLECULAR BIOSYSTEMS, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 7, no. 2, 1 February 2011 (2011-02-01), pages 359 - 364, XP002721196, ISSN: 1742-206X, [retrieved on 20100401], DOI: 10.1039/C0MB00074D *
GENNARO: "Remington: The Science and Practice of Pharmacy", 2000
GUZMAN ET AL., DOI: 10.1371/JOURNAL.PONE.0092444. ECOLLECTION, 2014
H. LIEBERMANL. LACHMAN: "Pharmaceutical Dosage Forms: Tablets", vol. 1, 1980, MARCEL DEKKER
JARMOSKAITE ET AL., HOW TO MEASURE AND EVALUATE BINDING AFFINITIES
LEINWEBER, DRUG METAB. RES., vol. 18, 1987, pages 379
LIANGCHEN, EXPERT OPINION IN THERAPEUTIC PATENTS, vol. 11, no. 6, 2001, pages 981 - 986
PATEL UMAR: "INVESTAGING THE ROLE OF KIFC1 AND CENTROSOME AMPLIFICATION IN PRIMARY AND METASTATIC UVEAL MELANOMA TOWARDS BUILDING A PROTAC TO TARGET KIFC1", 1 October 2019 (2019-10-01), XP093125747, Retrieved from the Internet <URL:https://eprints.lancs.ac.uk/id/eprint/139089/1/2019PatelMScRes.pdf> [retrieved on 20240131] *
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH
STEINEBACH CHRISTIAN ET AL: "A MedChem toolbox for cereblon-directed PROTACs", MEDCHEMCOMM, vol. 10, no. 6, 19 June 2019 (2019-06-19), United Kingdom, pages 1037 - 1041, XP055857543, ISSN: 2040-2503, DOI: 10.1039/C9MD00185A *
TROUP ROBERT I. ET AL: "Current strategies for the design of PROTAC linkers: a critical review", EXPLORATION OF TARGETED ANTI-TUMOR THERAPY, vol. 1, no. 5, 30 October 2020 (2020-10-30), XP055828975, Retrieved from the Internet <URL:https://www.explorationpub.com/uploads/Article/A100218/100218.pdf> DOI: 10.37349/etat.2020.00018 *
WU JIAQUAN ET AL: "Discovery and Mechanistic Study of a Small Molecule Inhibitor for Motor Protein KIFC1", ACS CHEMICAL BIOLOGY, vol. 8, no. 10, 16 August 2013 (2013-08-16), pages 2201 - 2208, XP093125668, ISSN: 1554-8929, DOI: 10.1021/cb400186w *

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