WO2021195706A1 - Nouveaux inhibiteurs de la dynamine et leurs utilisations - Google Patents

Nouveaux inhibiteurs de la dynamine et leurs utilisations Download PDF

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WO2021195706A1
WO2021195706A1 PCT/AU2021/050291 AU2021050291W WO2021195706A1 WO 2021195706 A1 WO2021195706 A1 WO 2021195706A1 AU 2021050291 W AU2021050291 W AU 2021050291W WO 2021195706 A1 WO2021195706 A1 WO 2021195706A1
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group
compound
alkyl
dynamin
disease
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David Almeida CARDOSO
Adam Mccluskey
Phillip James Robinson
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Children's Medical Research Institute
The University Of Newcastle
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Publication of WO2021195706A1 publication Critical patent/WO2021195706A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/28—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to methods of inhibiting dynamin activity and uses of new dynamin inhibitors.
  • Endocytosis refers to the invagination of the plasma membrane into cells, followed by the subsequent generation of a de novo phospholipid bilayer-encapsulated vesicle.
  • This physiological process is a means of: 1) incorporating extracellular objects for intracellular processing, 2) turnover or control of the state of membrane proteins that are exposed to the environment and 3) intracellular signal transduction (Besterman & Low, 1983, BiochemJ. 210, 1-13).
  • the internalised objects are known as cargo and may include: surface receptors, hormones, neurotransmitters, extracellular fluid and lower- order organisms (Doherty & McMahon, 2009, Annu.Rev.Biochem. 78, 857-902).
  • Dynamins are multi-domain GTPase enzymes capable of performing the final scission of invaginated plasma membrane prior to the completion of endocytosis Pharmacological targeting of dynamin in relevant mouse models has been shown to provide therapeutic relief for ailments as diverse as chronic kidney disease and epilepsy.
  • W02014063205 describes that dynamin inhibition enhances the antibody-dependent cellular cytotoxicity response, thus increasing the efficacy of immunotherapeutic agents.
  • the first reported dynamin inhibitors were long chain ammonium salts such as myristyl trimethyl ammonium bromide (MiTMAB), octadecyltrimethyl ammonium bromide (OcTMAB) (Hill et al. 2004) and dimeric tyrphostins such as Bis-T (Hill et al. 2005, J.Med.Chem. 48, 7781-7788). Later, a series of room temperature ionic liquids (RTILs) (Zhang et al. 2008, New Journal of Chemistry 32, 28-36) and dynasore (Macia et al. 2006, Dev Cell 10, 839-850) were reported.
  • RTILs room temperature ionic liquids
  • indole-based inhibitors termed “dynoles” (Hill et al. 2009, J.Med.Chem. 52, 3762-3773) and iminochromene-based inhibitors termed “iminodyns” have been reported (Hill et al. 2010, J.Med.Chem. 53, 4094-4102).
  • Most studies screening for dynamin inhibitors use GTPase assays whereby dynamin is maximally stimulated, and likely to be in its helical state.
  • Some of the most potent inhibitors from each of these series are also potent and reversible inhibitors of endocytosis in cells (Quan et al. 2007, Mol. Pharmacol. 72, 1425-1439; Hill et al. 2009, J.Med.Chem. 52, 3762-3773; Hill et al 2010, J.Med.Chem. 53, 4094-4102).
  • Dynamin and endocytosis inhibition have many potential therapeutic applications. For instance, as an adjuvant therapy, blocking endocytosis can improve cancer immunotherapy by increasing the surface exposure of proteins targeted by antibody therapies (Chew et al (2020) Cell 180, 895-914). Another illustration is that as a monotherapy, blocking endocytosis can reduce the infectivity of a broad range of viruses. Even those viruses that have direct fusion mechanisms can be delayed or show reduced infection when endocytosis or dynamin is inhibited (Aggarwal et al (2017), Traffic 18, 392-410).
  • the present disclosure is based in part on the surprising finding that a halo- diaminopyrimidine sulphonylbenzene compound of formula 1 or a salt thereof, inhibits dynamin activity.
  • the inventors have developed new methods and uses of inhibiting dynamin activity, and methods of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway.
  • a method of inhibiting dynamin activity comprising contacting a dynamin protein with a compound according to formula 1 or a salt thereof,
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is halogen.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and Ci-Ce alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is halogen; in the manufacture of a medicament for inhibiting dynamin activity in a subject.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 2 is C1-C6 alkyl;
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen; and X is halogen; for use in inhibiting dynamin activity in a subject.
  • a method of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway comprising the step of administering a compound of formula 1 or a salt thereof,
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-O, alkenyl, OR 2 and halogen
  • X is halogen; to a subject in need of such treatment.
  • Any of the methods disclosed herein may be a method of inhibiting dynamin activity in a cell.
  • the cell may be a mammalian cell.
  • the disease, disorder or condition may involve a dynamin mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • the disease or condition may be selected from the group consisting of epilepsy, viral infections, chronic kidney disease, chronic pain, Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy, cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down's syndrome (DS), heart failure (HF), and osteoporosis.
  • the disease, disorder or condition is a viral infection.
  • the viral infection may be an infection by a coronavirus.
  • the coronavirus is SARS-CoV-2.
  • the viral infection or coronavirus may be reduced or slowed in the subject.
  • any of the methods or uses disclosed herein may comprise the combined, separate or sequential administration of the compound according to formula 1 to the subject with a second therapeutic agent.
  • the second therapeutic agent may be an anti cancer agent.
  • the second therapeutic agent may comprise a monoclonal antibody.
  • the monoclonal antibody may be an antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody.
  • the second therapeutic agent may be an antiviral agent.
  • a method of treating a cancer involving a dynamin mediated pathway comprising the step of administering compound 2 or a salt thereof, in combination with a monoclonal antibody, to a subject in need of such treatment.
  • a method of treating a viral infection involving a dynamin-mediated pathway comprising the step of administering compound 2 or a salt thereof, to a subj ect in need of such treatment.
  • Any of the methods and uses disclosed herein may further comprise the step of determining dynamin activity after contacting the dynamin protein with the compound according to formula 1.
  • the dynamin activity may be any dynamin activity disclosed herein.
  • the dynamin activity may be dynamin mediated endocytosis and/or GTP hydrolysis.
  • Figure 3 Commercially available ceritinib-related drugs, (a) AP26113. (b) ASP3026. (c) AZD3436. (d) Brigatinib (e) Fedratinib. (f) TAE684.
  • Figure 5 Computational docking studies predict ceritinib binding to Hinge 1.
  • (b-e) Impact of Hinge 1 mutation on ceritinib action on helical dynamin GTPase activity (30 nM hdynlab, 150 mM GTP, 45 min assay time; n 2, technical triplicates)
  • Figure 6 Screen of a series of endocytosis inhibitors DC-01 (ceritinib), DC-02 (gilteritinib), DC-03 (NVP-TAE 684), Dynole 34-2 and Dyngo-4a for their ability to neutralise infection (% inhibition) of ACE2-expressing HEK293T cells by a pseudovirus expressing the SARS-CoV2 spike protein.
  • SEQ ID NO: 1 Amino acid sequence for a reference human dynamin I protein (Uniprot accession no. Q05193).
  • SEQ ID NO: 2 Amino acid sequence for a reference human dynamin II protein
  • SEQ ID NO: 3 Amino acid sequence for a reference human dynamin III protein (Uniprot accession no. Q9UQ16).
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • a bacterium includes a plurality of such bacteria
  • a reference to “a cell” includes populations of a plurality of cells
  • a reference to “an allergen” is a reference to one or more allergens.
  • range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 2, from 1 to 3, from 1 to 4, from 2 to 3, from 2 to 4, from 2 to 5, from 3 to 4 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, and 5. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.
  • administering should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • alkyl encompasses both straight-chain (i.e. linear) and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. In one example, the alkyl group is of one to six carbon atoms (i.e. Ci- 6 alkyl).
  • alkoxy refers to the group -O-alkyl, where “alkyl” is as described above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups.
  • the alkoxy group is of one to six carbon atoms (i.e. -O-Ci-6 alkyl).
  • alkoxy groups may be referred to as -OR 2 .
  • alkenyl refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups.
  • the alkenyl group is of two to six carbon atoms (i.e. C2- 6 alkenyl).
  • specific amine groups may be used to define the R 4 substituent and optional substituents of R 3 in formula 1.
  • the amine group is represented by-NR 5 2, where R 5 includes H, C1-C6 alkyl or C2-C6 alkenyl and may be the same or different.
  • piperidinyl or piperazinyl optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different” is used to define the R 3 substituent in formula 1.
  • piperidinyl refers to the piperidine group and the term “piperazinyl” refers to the piperazine group.
  • piperidinyl or piperazinyl are substituted with a piperidinyl or piperazinyl encompasses bicyclic combinations thereof where a piperidinyl group is bonded to a piperazinyl group.
  • the piperidinyl or piperazinyl group may also be optionally substituted with C1-C6 alkyl, C2- Ce alkenyl or -NR 5 2 as herein before defined. Substitution may occur at the nitrogen and/or carbon atoms.
  • the “piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NRV’ ofR 3 comprise:
  • Dynamin is a 96-kDa GTP-hydrolysing mechanoenzyme capable of concentration- and stimulus-dependent self-assembly. Assembly by oligomerisation stimulates its GTPase activity. The energy resulting from GTP hydrolysis allows dynamin to deliver a lipid fission-inducing power stroke, such as lipid fission at the neck of nascent endocytic vesicles (Chappie et al., 2011, Cell 147, 209-222).
  • DNM1, 2 and 3 Three dynamin genes (DNM1, 2 and 3) producing 3 proteins (I, II and III) and their alternatively spliced variants, which are differentially expressed in tissues and mediate a diverse range of physiological processes.
  • Exemplary reference amino acid sequences for DNM1, 2 and 3 are set forth in SEQ ID Nos: 1, 2 and 3, respectively.
  • This family is now referred to as the ‘classical dynamins’, since it was later shown to be part of a broader superfamily of large GTPase enzymes with diverse biological roles, primarily in lipid fission or fusion (Ramachandran,R. & Schmid, S.L. (2016) Curr.Biol. 28, R411-R416).
  • dynamin superfamily differ from the ras, rab and G-protein families of GTPases due to their modular structure, larger size (typically greater than 80 kDa) and their conserved propensity to self-assemble into rings or helices with assembly-stimulated GTPase activity.
  • the term “inhibit” shall be taken to mean hinder, reduce, restrain or prevent dynamin activity in a dynamin protein relative to dynamin activity in a dynamin protein, which has not yet been contacted with a compound of formula 1 or an acceptable salt thereof.
  • a method of inhibiting dynamin activity comprising contacting a dynamin protein with a compound according to formula 1 or a salt thereof.
  • a compound of formula 1 or an acceptable salt thereof in the manufacture of a medicament for inhibiting dynamin activity in a subject.
  • Also disclosed herein is a compound according to formula 1 or a salt thereof, for use in inhibiting dynamin activity in a subject.
  • the inhibition of dynamin activity may be a partial loss-of-function or a complete loss- of-function.
  • dynamin activity may be reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% following contact with a compound according to formula 1 or a salt thereof.
  • dynamin activity may be measured by measuring dynamin-mediated endocytosis in cells or body organs and/or GTP hydrolysis.
  • the dynamin activity is dynamin-mediated endocytosis.
  • the dynamin activity is GTP hydrolysis.
  • Dynamin-mediated endocytosis may be measured by assays such as transferrin endocytosis assays (Quan et al (2007), Mol. Pharmacol. 72, 1425-1439; McCluskey et al (2013), Traffic 14, 1272-1289; Robertson et al (2014), Nat.Protoc. 9, 1592-1606), EGF endocytosis assays or antibody binding assays.
  • dynamin activity may be measured in vitro by GTPase activity assays (Quan and Robinson 2005, Methods Enzymol. 404 (Ch 49), 556-569).
  • the methods disclosed herein may be performed in a cell.
  • the cell may be a mammalian cell.
  • the cell may be in vivo or in vitro.
  • a compound of formula 1 or a salt thereof is useful in a method of inhibiting dynamin activity.
  • the present disclosure includes a method of preventing disease, disorder or condition involving a dynamin mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • Use of a compound of formula 1 or a salt thereof in the manufacture of a medicament for inhibiting dynamin activity in a subject is also disclosed.
  • Embodiments of the methods and uses described herein comprise administering a compound of formula 1, or a salt thereof.
  • a compound of formula 1 has the following chemical structure: or a salt thereof, wherein
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is Ci-Ce alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C2-C6 alkenyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is propyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is butyl. In some embodiments, R 1 is tert-butyl. In some embodiments, R 1 is pentyl. In some embodiments, R 1 is hexyl. In some embodiments, R 1 is ethenyl. In some embodiments, R 1 is propenyl. In some embodiments, R 1 is butenyl. In some embodiments, R 1 is pentenyl. In some embodiments, R 1 is hexenyl.
  • R 2 is isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is hexyl.
  • R 3 is piperidinyl or piperazinyl optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2, wherein the piperidinyl and piperazinyl substituent may be optionally substituted with one or more of the group consisting C1-C6 alkyl, C1-C6 alkenyl and -NR 5 2 .
  • R 3 is piperidinyl substituted with piperazinyl optionally substituted with C1-C6 alkyl, C2-C6 alkenyl or -NR 5 2.
  • R 3 is piperidynyl substituted with piperazinyl substituted with C1-C6 alkyl. In some embodiments, R 3 is piperidynyl substituted with piperazinyl substituted with methyl. In some embodiments, R 3 is piperidinyl. In some embodiments, R 3 is piperidinyl substituted with -NR 5 2. In some embodiments, R 3 is piperidinyl substituted with -NHz In some embodiments, R 3 is piperazinyl optionally substituted with piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl or -NR 5 2. In some embodiments, R 3 is piperazinyl substituted with methyl. In some embodiments, R 3 is selected from the group consisting of: In some embodiments, R 3 is In some embodiments, R 3 is s, R 3 is
  • R 4 is C1-C6 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is iso-propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is tert-butyl. In some embodiments, R 4 is pentyl. In some embodiments, R 4 is hexyl. In some embodiments, R 4 is C2-C6 alkenyl. In some embodiments, R 4 is ethenyl. In some embodiments, R 4 is propenyl. In some embodiments, R 4 is butenyl.
  • R 4 is pentenyl. In some embodiments, R 4 is hexenyl. In some embodiments, R 4 is -NR 5 2 In some embodiments, R 5 is the same. In some embodiments, R 5 is different. In some embodiments, R 4 is -N ⁇ 2. In some embodiments, R 4 is - NH(methyl). In some embodiments, R 4 is -NH(propyl). In some embodiments, R 4 is - NH(iso-propyl). In some embodiments, R 4 is -NH(tert-butyl). In some embodiments, R 4 is -NH(pentyl). In some embodiments, R 4 is -NH(hexyl).
  • R 5 is H. In some embodiments, R 5 is Ci-Ce alkyl. In some embodiments, R 5 is C2-C6 alkenyl. In some embodiments, R 5 is H. In some embodiments, R 5 is tert-butyl.
  • R 6 is selected from one or more of the group consisting ofH, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen.
  • R 6 is H.
  • R 6 is methyl.
  • R 6 is ethyl.
  • R 6 is propyl.
  • R 6 is butyl.
  • R 6 is tert-butyl.
  • R 6 is pentyl.
  • R 6 is hexyl.
  • R 6 is C2-C6 alkenyl.
  • R 6 is ethenyl.
  • R 6 is propenyl.
  • R 6 is butenyl. In some embodiments, R 6 is pentenyl. In some embodiments, R 6 is hexenyl. In some embodiments, R 6 is O-methyl. In some embodiments, R 6 is O-ethyl. In some embodiments, R 6 is O-propyl. In some embodiments, R 6 is O-butyl. In some embodiments, R 6 is O-tert-butyl. In some embodiments, R 6 is O-pentyl. In some embodiments, R 6 is O-hexyl. In some embodiments, R 6 is O-ethenyl, O-propenyl, O-butenyl, O-pentenyl or O-hexeny. In some embodiments, R 6 is Cl. In some embodiments, R 6 is FI. In some embodiments, R 6 is Br. In some embodiments, R 6 is I. In some embodiments, R 6 is Cl. In some embodiments, R 6 is CN.
  • X is Cl. In some embodiments, X is FI. In some embodiments, X is Br. In some embodiments, X is I. In some embodiments, X is Cl. In some embodiments, X is CN.
  • the compound of formula 1 includes any stereoisomers of the depicted structure.
  • the compound of formula 1 includes a racemic mixture.
  • the compound of Formula 1 has the four distinct features of i) a halo diaminopyrimidine group, ii) a sulphonylbenzene group, iii) an alkoxyl benzene group, and iv) a piperidinyl and/or piperazinyl group.
  • the compound of formula 1 is compound 2:
  • Compound 2 is also referred to as “ceritinib” or LDK378 and has CAS No.: 1032900- 25-6.
  • the chemical name (i.e., IUPAC name) of compound 2 is 5-chloro-2-/V-(2- isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-4-/V-(2-(isopropylsulfonyl)phenyl) pyrimidine-2, 4-diamine.
  • Compound 2 is commercially available from a number of manufacturers including Cayman Chemical and LC Laboratories. Compound 2 has previously been shown to be an inhibitor of the protein kinase ALK (Marsilje et al (2013) J.Med.Chem. 56, 5675- 5690). It has been approved for the treatment of certain cancers, for example, metastatic non-small cell lung cancer (NSCLC), whose tumours are ALK-positive.
  • NSCLC metastatic non-small cell lung cancer
  • compound 2 or a salt thereof may be prepared by any suitable method as would be understood by the person skilled in the art.
  • Compound 2, or a salt, thereof may be prepared according to the appropriate procedure given in the literature, such as that described in US8,039,479 and Marsilje TH, et al, Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-2-N-(2-isopropoxy-5-methyl-4-(piperidin-4- yl)phenyl)-4-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-2, 4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials, J Med Chem. 2013 Jul 25;56(14) 5675- 90, or the like.
  • ALK anaplastic lymphoma kinase
  • the compound of formula 1 is compound 3 or a salt thereof:
  • Compound 3 is also referred to as “TAE684” or NVP-TAE684 and has CAS No.: 761439-42-3.
  • the chemical name (i.e., IUPAC name) of compound 3 is 5-chloro-2-/V-
  • Compound 3 or salt thereof may be prepared by any suitable method as would be understood by the person skilled in the art.
  • Compound 3 or a salt thereof may be prepared according to the appropriate procedure given in the literature, such as that described in US8,039,479, J Med Chem. 2013 Jul 25:56(14) 5675-90 or the like.
  • a compound of formula 1 or a salt thereof, as herein described, for use in inhibiting dynamin activity for use in inhibiting dynamin activity.
  • the salt may be in the form of a “pharmaceutically acceptable salt” which refers to pharmaceutically acceptable organic or inorganic salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., vol. 66, pl-19.
  • salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N'- dibenzyl ethyl enedi amine salt and the like.
  • organic acid salts such as formate, a
  • acceptable excipient includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to a compound as described herein or use thereof.
  • excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to a compound as described herein or use thereof.
  • the use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, for example Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005).
  • compositions for the administration of the compound of formula 1 of this disclosure may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.
  • compositions and methods disclosed herein may further comprise other therapeutically active compounds which are usually applied in the treatment of the disclosed disorders or conditions.
  • Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to affect the treatment or prevention of the various disorders or conditions disclosed herein. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • the inventors have surprisingly shown for the first time that compounds of formula 1 or a salt thereof, inhibit dynamin activity. Based on this finding, the inventors have developed and provide herein, (i) methods of inhibiting dynamin activity and (ii) methods of treating or preventing a disease, disorder or condition involving a dynamin- mediated pathway.
  • a method of inhibiting dynamin activity comprising contacting a dynamin protein with a compound according to formula 1, or a salt thereof, wherein R 1 is selected from the group consisting of H, C1-C6 alkyl and Ci-Cr, alkenyl;
  • R 2 is Ci-Ce alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, Ci-Ce alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, Cri-Cr, alkenyl and
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen; and
  • X is halogen.
  • the dynamin activity is dynamin mediated endocytosis.
  • the dynamin activity is GTP hydrolysis.
  • the dynamin activity is dynamin-mediated endocytosis and GTP hydrolysis.
  • a method of inhibiting dynamin activity in a mammalian cell in some embodiments, there is provided a method of inhibiting dynamin activity in a mammalian cell.
  • a method of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway in a subject having or susceptible to the disease, disorder or condition in some embodiments, there is provided a method of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C 6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • the dynamin activity is GTP hydrolysis. In some embodiments, the dynamin activity is dynamin mediated endocytosis and/or GTP hydrolysis.
  • the medicament is for treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • a method of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway comprising the step of administering a compound of formula 1 or salt thereof, wherein
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • treating refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • the term “subject” refers to any animal, for example, a mammalian animal, including, but not limited to humans, non-human primates, livestock (e g. sheep, horses, cattle, pigs, donkeys), companion animals (e.g. pets such as dogs and cats), laboratory test animals (e.g. mice, rabbits, rats, guinea pigs), performance animals (e.g. racehorses, camels, greyhounds) or captive wild animals
  • livestock e g. sheep, horses, cattle, pigs, donkeys
  • companion animals e.g. pets such as dogs and cats
  • laboratory test animals e.g. mice, rabbits, rats, guinea pigs
  • performance animals e.g. racehorses, camels, greyhounds
  • captive wild animals e.g. racehorses, camels, greyhounds
  • the “subject” is a human.
  • the terms “subject” and “patient” are used interchangeably, particularly in reference to
  • the subject may be receiving combined, separate or sequential administration of a second therapeutic agent
  • the methods disclosed herein may be a method of treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • the disease, disorder or condition may be directly or indirectly mediated by dynamin.
  • dynamin mediated endocytosis may be disrupted by upstream or downstream effectors and may not require the direct involvement of dynamin.
  • blocking dynamin- mediated endocytosis may have an impact on the disease, disorder or condition or on the agents treating disease, disorder or condition.
  • CMT Charcot-Marie-Tooth disease
  • centronuclear myopathy Zuchner,S., Noureddine,M., Kennerson,M., Verhoeven,K., Claeys,K., Jonghe,P.D., Merory ., Oliveira, S. A., Speer, M.C., Stenger,J.E., Walizada,G., Zhu,D., Pericak-Vance,M.A., Nicholson, G.A., Timmerman, V. & Vance, J.M. (2005) Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat. Genet.
  • Dynamin 2 potentiates invasive migration of pancreatic tumor cells through stabilization of the Racl GEF Vavl. Dev Cell 24, 573-585.; Luwor,R.B., Morokoff,A.P., Amiridis,S., D'Abaco,G., Paradiso,L., Stylli,S.S., Nguyen, H.P.T., Tarleton,M., Young, K.
  • the cancer may be head and neck cancer.
  • AD Alzheimer’s disease
  • Circular RNA NF1-419 enhances autophagy to ameliorate senile dementia by binding dynamin- 1 and adaptor protein 2 B1 in AD-like mice.
  • osteoporosis Melat,Y., Takagi,T., Hirota,M., Yamada,J., Ishihara,S., Yung,T.M., Inoue,T., Sawa,C., Sagara,H., Sakamoto, S., Kabe,Y., Takahashi,Y., Yamaguchi,Y. & Handa,H. (2009) Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates. Mol. Pharmacol. 77, 262-299.
  • a dynamin modulator can be either as a monotherapy (Luwor,R.B., Morokoff,A.P., Amiridis,S., D'Abaco,G., Paradiso,L., Stylli, S. S., Nguyen,H.P.T., Tarleton,M., Young, K.A., O'Brien, T.J., Robinson, P.J., Chircop,M., McCluskey,A. & Jones, N.C. (2019) Targeting glioma stem cells by functional inhibition of dynamin 2: A novel treatment strategy for glioblastoma.
  • the methods disclosed herein may be a method of treating cancer.
  • the cancer may be head and neck cancer.
  • the cancer may be a cancer involving anaplastic lymphoma kinase (ALK) or a cancer that does not involve ALK.
  • the cancer may be a cancer involving ALK (i.e. an ALK-positive cancer).
  • the cancer does not involve ALK (i.e. an ALK-negative cancer).
  • the methods disclosed herein may be a method of treating a viral infection.
  • Viral infections involving a dynamin-mediated pathway are known in the art (Harper, C.B., Popoff,M.R., McCluskey,A., Robinson, P.J. & Meunier,F.A. (2013) Trends Cell Biol. 23, 90-101).
  • the present inventors and others have shown that infection by several viruses can be reduced or slowed in part with dynamin or endocytosis inhibitors, see:
  • HIV infection is influenced by dynamin at three independent points in the viral life cycle. Traffic 18, 392- 410., PMID:28321960)
  • prochlorperazine sold as Stemetil
  • Stemetil Diel, J.A., Chau,N., Abdel- Hamid,M.K., Hu,L., von Kleist,L., Whiting, A., Krishnan,S., Maamary,P., Joseph, S.R., Simpson, F., Haucke,V., McCluskey,A. & Robinson, P.J. (2015) Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis. Traffic 15, 635- 654.).
  • the viral infection is an infection by a coronavirus.
  • Coronaviruses are group of related viruses that can cause respiratory tract infections, which can be mild (e.g. the common cold) or possibly lethal such as SARS, MERS and COVID-19.
  • the coronavirus may be SARS-CoV-2.
  • the present disclosure contemplates reducing or slowing down a viral infection in a subject suffering from such a condition by treating the subject with a compound of formula 1 or a salt thereof as hereinbefore defined.
  • the present disclosure contemplates reducing or slowing down a viral infection in a subject suffering from such a condition by treating the subject with compound 2 (ceritinib): 2 or a salt thereof.
  • the viral infection may be an infection by a coronavirus.
  • the coronavirus may be SARS-CoV-2.
  • the methods or uses disclosed herein may comprise the combined, separate or sequential administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the methods or uses disclosed herein may comprise the combined administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the methods or uses disclosed herein may comprise separate administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the methods or uses disclosed herein may comprise sequential administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the methods or uses disclosed herein may not comprise the combined, separate or sequential administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the methods or uses disclosed herein may comprise the combined, separate or sequential administration of the compound according to formula 1 or salt thereof to the subject with a second therapeutic agent.
  • the second therapeutic agent may be an agent with any known modality.
  • the second therapeutic agent may be surgery, radiotherapy, chemotherapy or immunotherapy.
  • the second therapeutic agent may be an anti -cancer agent.
  • Anti -cancer agents are known in the art.
  • the anti-cancer agent is a monoclonal antibody.
  • a method of treating cancer comprising administering the compound according to formula 1 or salt thereof to the subject, wherein the subject is receiving combined, separate or sequential administration of a monoclonal antibody.
  • the compound according to formula 1 or salt thereof may be ceritinib.
  • the monoclonal antibody may be selected from the group consisting of avelumab, cetuximab and trastuzumab.
  • the monoclonal antibody is avelumab.
  • the monoclonal antibody is cetuximab.
  • the monoclonal antibody is trastuzumab.
  • the second therapeutic agent may be an anti-viral agent.
  • Anti-viral agents are known in the art. It will be understood by the person skilled in the art that anti-viral agents work through a variety of mechanisms. For example, anti-viral agents may be agents that block viral replication. Alternatively or in addition, anti-viral agents may be agents that interfere with the binding of the virus coat protein to human cell receptors or directly to the cell surface. Alternatively or in addition, anti-viral agents may be agents that block the escape of viral particles from the endosome/lysosome system.
  • anti-viral agents include, but are not limited to, spike protein attachment inhibitors, protease inhibitors, antiviral interferons, chemokine receptor antagonists, integrase strand transfer inhibitors, neuraminidase inhibitors, non-nucleoside reverse transcriptase inhibitors ( NRTIs), non-structural protein 5A (NS5A), nucleoside reverse transcriptase inhibitors (NRTIs), and purine nucleosides.
  • spike protein attachment inhibitors include, but are not limited to, spike protein attachment inhibitors, protease inhibitors, antiviral interferons, chemokine receptor antagonists, integrase strand transfer inhibitors, neuraminidase inhibitors, non-nucleoside reverse transcriptase inhibitors ( NRTIs), non-structural protein 5A (NS5A), nucleoside reverse transcriptase inhibitors (NRTIs), and purine nucleosides.
  • NRTIs non-nucleo
  • antibody herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multi specific antibodies (e.g. bispecific antibodies), antibody fragments (e g. nanobody), or any other antigen-binding molecule so long as they exhibit the desired biological activity.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones or recombinant DNA clones.
  • the selected target binding sequence can be further altered, for example, to improve affinity for the target, to humanize the target binding sequence, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered target binding sequence is also a monoclonal antibody of this invention.
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.
  • the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler et ah, Nature, 256:495 (1975); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et ah, in: Monoclonal Antibodies and T-Cell Hybridomas 563-681, (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No.
  • phage display technologies see, e.g., Clackson et ah (1991) Nature 352:624-628; Marks et ah (1991) J. Mol. Biol. 222:581- 597; Sidhu et ah (2004) J. Mol. Biol. 338(2):299-310; Lee et ah (2004) J. Mol. Biol. 340(5): 1073- 1093; Fellouse (2004) Proc. Nat. Acad. Set USA 101(34): 12467-12472; and Lee et ah (2004) J. Immunol.
  • Methods 284(1-2): 119- 132 and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741 ; jakobovits et al. (1993) Proc. Natl. Acad. Sci. USA 90:2551 ; Jakobovits et al. (1993) Nature 362:255- 258; Bruggemann et al. (1993) Year in Immuno. 7:33; U S. Pat. Nos.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; and Morrison et al. (1984) Proc. Natl. Acad. Sci. USA 81 :6851-6855).
  • Chimeric antibodies of interest herein include "primatised” antibodies comprising variable domain antigen binding sequences derived from a non-human primate (e.g., Old World Monkey, Ape etc.) and human constant region sequences, as well as “humanized” antibodies.
  • a non-human primate e.g., Old World Monkey, Ape etc.
  • human constant region sequences e.g., human constant region sequences, as well as “humanized” antibodies.
  • Humanized forms of non-human (e.g. rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • donor antibody such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Antibody fragments comprise a portion of an intact antibody, suitably comprising the antigen binding region thereof.
  • antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragment(s).
  • an antibody “that binds" an antigen of interest is one that binds the antigen with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins.
  • the extent of binding of the antibody to a "non-target" protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation assay (RIA).
  • the term "specific binding” or “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction.
  • Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.
  • specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target.
  • the monoclonal antibody may be an antibody-dependent cellular cytotoxicity (ADCC)- mediating antibody. It will be understood that an ADCC-mediating antibody induces an ADCC response in a subject.
  • ADCC antibody-dependent cellular cytotoxicity
  • Antibody-dependent cell-mediated cytotoxicity and “ADCC” refer to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell.
  • FcRs Fc receptors
  • FcR expression on hematopoietic cells in summarized is Table 3 on page 464 of Ravetch and Kinet, (1991) Annu. Rev. Immunol. 9:457-92.
  • ADCC activity of a molecule of interest may be assessed in vitro, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337.
  • useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells.
  • PBMC peripheral blood mononuclear cells
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. (1998) Proc. Natl. Acad. Sci. USA 95:652- 656.
  • the monoclonal antibody may be selected from the group consisting of avelumab, cetuximab and trastuzumab.
  • the monoclonal antibody is avelumab.
  • the monoclonal antibody is cetuximab.
  • the monoclonal antibody is trastuzumab.
  • the medicament consists essentially a compound of formula 1 or a salt thereof.
  • the medicament or the composition may also include excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to the inhibitor as described herein or use thereof.
  • excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to the inhibitor as described herein or use thereof.
  • the use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, for example Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005).
  • Also disclosed herein is a method of treating or preventing a disease, disorder or condition involving a
  • a therapeutically effective amount of a compound of formula 1 or a salt thereof may be used.
  • therapeutically effective amount refers to a compound of formula 1, or a salt thereof being administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated, typically without undue adverse side effects or to achieve a desired pharmacological effect or therapeutic improvement with a reduced side effect profile. The results can be the reduction and/or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system.
  • therapeutically effective amount refers to a compound of formula 1, or a salt thereof, being administered in an amount sufficient to result in a reduction of symptoms associated with the disease, disorder or condition.
  • Therapeutically effective amounts may, for example, be determined by routine experimentation, including but not limited to a dose escalation clinical trial.
  • the phrase “therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • the amount of a compound of formula 1, or salt thereof, that will be effective in the treatment and/or prevention of a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques.
  • in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Such techniques are known to the person skilled in the art.
  • the compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered in an amount so as to deliver a total daily dosage (in mg) of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, 200, 300, 400, 500, 600 , 700.
  • the compound of formula 1, or a pharmaceutically acceptable salt thereof is administered in an amount so as to deliver a total daily dosage (in mg) of less than about 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1.
  • the total daily dosage may be provided in a range between at any two of these upper and/or lower amounts.
  • a total daily dosage may be provided in an amount of between about 1 and 100 mg, about 5 and 75 mg, about 10 and 50 mg, about 15 and 45 mg, or about 20 and 40 mg.
  • a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof is administered to the subject at a predetermined frequency.
  • a compound of formula 1, or a pharmaceutically acceptable salt thereof is administered to the subject according to a dosage regimen in which a compound of formula 1, or a pharmaceutically acceptable salt, is administered once daily, twice daily, three times daily, or four times daily.
  • a compound of formula 1, or a pharmaceutically acceptable salt is administered to the subject according to a dosage regimen in which a compound of formula 1, or a pharmaceutically acceptable salt, is administered multiple times daily.
  • a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt is administered to the subject at a predetermined frequency and/or duration.
  • administration according to any embodiments (e g. frequency) as described herein may be for a duration of about, or at least about, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 2 years, or 5 years.
  • Administration of the therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be ongoing so long as a therapeutic effect is received by the subj ect.
  • ceritinib for treating other diseases.
  • about 750 mg of ceritinib may be administered once daily.
  • about 450 mg of ceritinib may be administered daily.
  • about 350 mg of ceritinib may be administered daily.
  • about 150 mg of ceritinib may be administered daily.
  • the dosage may be about 150mg in capsule form.
  • the ceritinib may be administered orally in capsule form.
  • ceritinib may be administered with food.
  • the present disclosure also provides a kit comprising a compound of formula 1 and a second therapeutic agent such as an anti-cancer agent for treating cancer or an anti-viral agent for treating a viral infection.
  • the kit may contain instructions for use.
  • a method of inhibiting dynamin activity comprising contacting a dynamin protein with a compound according to formula 1 or a salt thereof, wherein R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • the disease, disorder or condition is selected from the group consisting of epilepsy, viral infections, chronic kidney disease, chronic pain, Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy, cancer including head and neck cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down syndrome (DS), heart failure (HF), and osteoporosis.
  • CMT Charcot-Marie-Tooth disease
  • CMT Charcot-Marie-Tooth disease
  • CMT Charcot-Marie-Tooth disease
  • centronuclear myopathy cancer including head and neck cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down syndrome (DS), heart failure (HF), and osteoporosis.
  • the second therapeutic agent comprises a monoclonal antibody.
  • the monoclonal antibody is an antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • embodiment 17 or embodiment 18, wherein the medicament is for treating or preventing a disease, disorder or condition involving a dynamin-mediated pathway in a subject having or susceptible to the disease, disorder or condition.
  • the disease, disorder or condition is selected from the group consisting of epilepsy, viral infections, chronic kidney disease, chronic pain, Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy, cancer including head and neck cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down syndrome (DS), heart failure (HF), and osteoporosis.
  • CMT Charcot-Marie-Tooth disease
  • CMT Charcot-Marie-Tooth disease
  • CMT Charcot-Marie-Tooth disease
  • centronuclear myopathy cancer including head and neck cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down syndrome (DS), heart failure (HF), and osteoporosis.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 2 is C1-C6 alkyl
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different; R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen; and X is a halogen; for use in inhibiting dynamin activity in a subject.
  • the disease, disorder or condition is selected from the group consisting of epilepsy, viral infections, chronic kidney disease, chronic pain, Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy, cancer including head and neck cancer, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, Down syndrome (DS), heart failure (HF), and osteoporosis.
  • the disease, disorder or condition is a viral infection.
  • a method of treating or preventing a disease, disorder or condition involving a dynamin mediated pathway comprising the step of administering a compound of formula 1 or a salt thereof, wherein
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 2 is C1-C6 alkyl;
  • R 3 is a piperidinyl or piperazinyl, optionally substituted with one or more of the group consisting of piperidinyl, piperazinyl, C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 4 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl and -NR 5 2 wherein R 5 is the same or different;
  • R 5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen
  • X is a halogen
  • R 1 is selected from the group consisting of H, methyl or ethyl
  • R 2 is selected from the group consisting of methyl, ethyl, propyl or isopropyl;
  • R 4 is selected from the group consisting of isopropyl and -NH(tert-butyl);
  • R 6 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen;
  • a method of treating a viral infection involving a dynamin mediated pathway comprising the step of administering compound 2,
  • a panel of clinical protein kinase inhibitors was selected from 243 clinically used protein kinase inhibitors (Klaeger et al., 2017, Science 358, eaan4368) for evaluation of their potential activity against dynamin GTPase activity and endocytosis.
  • the following clinical kinase compounds were evaluated: ceritinib, crizotinib, ensartinib, imatinib, KW2449, refametinib, vemurafenib, AP26113, ASP3026, AZD3436, briatinib, fedratinib and TAE684.
  • Example 1 General materials
  • the malachite green phosphate detection assay is a reliable, colorimetric, absorbance- based experimental method capable of measuring inorganic free phosphate in aqueous solution within a 96-well plate context (in vitro, Quan,A. & Robinson, P.J. (2005) Methods Enzymol. 404 (Ch 49), 556-569).
  • a 40 pL volume of malachite green solution (2% (w/v) ammonium molybdate tetrahydrate, 0.15% (w/v) malachite green, 4 M HC1) was then added and the assay shaken for a further 5 min at 800 rpm to promote malachite green molybdate-inorganic phosphate complexes.
  • the absorbance (650 nm) was measured and raw data exported for further analysis.
  • the reaction details described above are the basal dynamin GTPase activity assay.
  • the assays were modified to include phosphatidylserine liposomes or SNX9-SH3 domain (1 in 100 dilution for both) stimulation of dynamin to helices or rings, respectively.
  • All activity assays using SNX9-SH3 domain involved a 60 min pre-incubation on ice prior to initiation (incubation at 37°C with 800 rpm shaking) due to the necessity of such a period to allow for dynamin ring formation.
  • Pi is a common contaminant of water and commercially sourced chemicals and can interfere with all malachite green-based assays. Therefore, its presence was considered in all reagents used in this assay and subtracted. Thus, salt-adjusted buffer alone was subtracted from all reaction wells. If small molecules were used in the assay, the resultant colourimetric absorbance value of the drug alone (no dynamin) was a standard part of all assays and was subtracted accordingly from values where drug plus dynamin were present. Mean and SEM were calculated and the specific activity of dynamin was plotted as a function of drug concentration or incubation time. Important parameters such as IC50 and ECso curves were generated by fitting a non-linear regression equation to the relevant drug-response curves.
  • U20S line unmodified human bone osteosarcoma epithelial cells
  • DMEM fetal bovine serum
  • Transferrin uptake via CME was performed using a high-throughput (single plane, no cell modification) protocol. Given the suitable characteristics of the U20S cell line, they were utilised for high-throughput screening of endocytosis inhibitors (e.g. dyngo/ryngo, carbazole scaffolds and protein kinase inhibitors).
  • endocytosis inhibitors e.g. dyngo/ryngo, carbazole scaffolds and protein kinase inhibitors.
  • a cold, low pH (0.2 M acetic acid, 0.5 MNaCl, pH 2.8) acid wash (with 10 min incubation) was applied to strip residual transferrin from the cell surface.
  • a further cold PBS wash (with 5 min incubation) was undertaken to restore extracellular pH.
  • the percentage of endocytosis (relative to that in DMSO-treated control cells) was plotted as a function of small molecule concentration and non-linear regression was applied to determine the IC50 value. Acquired images were visually assessed as a secondary validation of the results. One such example is checking for signs of overall cell health as drug toxicity at higher concentrations may have the potential to conflate toxicity and drug-mediated endocytosis block (via dynamin) when assessing transferrin uptake. Recording instances of cell lifting (likely due to toxicity) and dye aggregation (observed in some drug treatments) are important to ensure the automated image analysis is accurate.
  • Ceritinib is a potent inhibitor of helical dynamin activity
  • An initial panel of seven clinical kinase drugs (Ceritinib, Crizotinib, Ensartinib, Imatinib, KW2449, Refametinib and Vemurafenib) were investigated (Figure 1). They were first tested in vitro against helical dynamin GTPase activity (i.e. activity stimulated by lipids). Five of the compounds in this targeted panel inhibited dynamin, with only refametinib and vemurafenib being inactive in the concentration range tested (Table 1).
  • ceritinib had an ICso of 2.3 ⁇ 0.1 pM (Table 1, Figure 2a). The potency of ceritinib is striking, being twice that of any compound used in this study.
  • Ceritinib is a potent endocytosis inhibitor
  • ceritinib is an ATP-competitive inhibitor for ALK. Ceritinib binds in the active site, at the interface of N- and C-lobes, being located under the glycine-rich phosphate-binding loop (P-loop) (Ni et al., 2016, Comput Biol Chem 65, 54-60). This raises the possibility that it may also be competitive with dynamin’ s GTP binding site. Therefore, a check was done to determine if ceritinib ’s mechanism of action on dynamin was competitive with the substrate GTP. The ICso values at all tested concentrations were essentially unchanged, providing good preliminary evidence that the compound is not competitive with respect to GTP binding at the G domain ( Figure 4). Therefore, ceritinib is likely an allosteric modulator of dynamin.
  • Ceritinib was identified as the most potent dynamin inhibitor in the panel of compounds evaluated with TAE 684 identified as the next most potent dynamin inhibitor. Both compounds were also potent endocytosis inhibitors.
  • the SAR of these two compounds reveals four distinct common structural features: i) a chloro diaminopyrimidine group, ii) a sulphonylbenzene group, iii) an alkoxyl benzene group, and iv) a piperidinyl or piperazinyl group. In the entire panel of compounds tested, these two compounds are the only two that possess these four unique features. Importantly, the positioning and connectivity of these four groups within the structure is also similar.
  • crizonitib, ensartinib, KW2449 and AZD3436 displayed moderate dynamin and endocytosis activity.
  • no one of these compounds contained all four of the structural features noted above or the connectivity order of ceritinib and TAE684.
  • AP26113 brigatinib, fedratinib, reametinib and vemurafenib showed no dynamin inhibition.
  • R 1 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl;
  • R 2 is C1-C6 alkyl
  • R 5 is selected from the group consisting of H, C1-C6 alkyl or C2-C6 alkenyl
  • R 6 is selected from one or more of the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, OR 2 and halogen;
  • X is a halogen
  • Example 4 Inhibition of SARS-CoV2 by endocytosis inhibitors
  • DC-01 ceritinib
  • DC-02 gilteritinib
  • DC-03 NBP- TAE 684
  • Dynole 34-2 and Dyngo-4a were screened for their ability to neutralise infection (% inhibition) of ACE2-expressing HEK293T cells by a pseudovirus expressing the SARS-CoV2 Spike protein.
  • Endocytosis inhibitors were prepared from powder in 30 mM (except DC-01/ ceritinib, 10 mM) stock solutions with 100% DMSO. Endocytosis inhibitors were serially diluted, 4-fold, from 200 mM to 0.2 pM. Endocytosis inhibitor dilutions were added to monoclonal HEK293T cells engineered to express ACE2 and incubated for lh at 37°C, 5% C02. SARS-CoV2 spike protein expressing pseudovirus (spike pseudo) containing a GFP expression cassette was added to the cells + inhibitors and infection was performed by spinoculation for lh at 35°C, 800g. Three days later the ACE2. HEK293T cells were stained with nuclear stain DAPI and the percentage of cells expressing GFP was determined.
  • Figure 6 shows that all the dynamin and endocytosis inhibitors tested achieved an IC50 value within the concentration range used.
  • Dynole 34-2, and Dyngo-4a were used as published positive controls for dynamin and endocytosis inhibitors. This could not be attributed to the DMSO, as 0.66% DMSO (the amount in the 200 pM samples) only reduced the number of nuclei by half.
  • Compounds that enhanced spike pseudovirus infection at 200 pM shown as reduced %inhibition, or downward deflection in the graph) also enhanced VSV.G expressing pseudovirus infection, indication non specificity of action.
  • Overall the data shows Ceritinib and Dynole 34-2 to be potent antivirals in this assay.

Abstract

La présente invention concerne de manière générale l'utilisation de composés d'halodiaminopyrimidine sulfonylbenzène dans le traitement ou la prévention de maladies, de troubles ou d'états impliquant une voie médiée par la dynamine.
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