WO2024040241A1 - Formulations pharmaceutiques, processus de préparation et méthodes d'utilisation - Google Patents

Formulations pharmaceutiques, processus de préparation et méthodes d'utilisation Download PDF

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Publication number
WO2024040241A1
WO2024040241A1 PCT/US2023/072503 US2023072503W WO2024040241A1 WO 2024040241 A1 WO2024040241 A1 WO 2024040241A1 US 2023072503 W US2023072503 W US 2023072503W WO 2024040241 A1 WO2024040241 A1 WO 2024040241A1
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Prior art keywords
pharmaceutical formulation
compound
amount
formula
polymer carrier
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PCT/US2023/072503
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English (en)
Inventor
Mehdi Paborji
Biljana Nadjsombati
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Viracta Therapeutics, Inc.
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Publication of WO2024040241A1 publication Critical patent/WO2024040241A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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 3 -phosphoinositide-dependent protein kinase- 1 (PDK1, also known as PDPK1) is a master kinase that activates other kinases important in cell growth and survival including members of the Akt (protein kinase B, PKB), protein kinase C (PKC), p90 ribosomal S6 kinase RSK (S6K), and SGK families.
  • PDK1 activates substrate kinases via activation T- loop phosphorylation.
  • PDK1 is a 556-amino acid protein that consists of an N-terminal kinase (catalytic) domain, and a C-terminal pleckstrin homology (PH) domain.
  • the PH domain interacts with phosphatidylinositol (PI) (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, contributing to localization and activation of certain PDK1 substrates, notably including Akt.
  • PI phosphatidylinositol
  • Akt phosphatidylinositol
  • the activation of Akt is believed to require a proper orientation of the kinase and PH domains of PDK1 and Akt at the membrane.
  • Akt is itself known to be associated with cancers, and is frequently mutated or hyperactivated in human cancers.
  • PDK1 can interact with certain of its substrates through this PI-dependent (PH-mediated) mechanism, it can interact with other substrates through a distinct Pl-indep endent mechanism.
  • the N-terminal kinase domain has three ligand binding sites; a substrate binding site, an ATP binding site, and a docking site (also known as PIF pocket) for interaction with substrates.
  • This docking site is known as the “PIF pocket,” referring to its binding to a region of protein kinase C-related kinase-2 (PRK2), termed the PDK1- interacting fragment (PIF).
  • PRK2 protein kinase C-related kinase-2
  • PDK1 is important in regulating the activity of other kinases. Of the several known PDK1 substrates, much attention has focused on AKT. Development of potent and selective AKT inhibitors has been challenging. Studies have revealed, surprisingly, that many tumor types are not sensitive to AKT inhibition or express no or little activated AKT. [0005] PDK1 is the only kinase known to phosphorylate Thr308 in the activation loop of AKT that is critical for activation of AKT kinase. Thus, PDK1 plays a critical role in AKT activation. Efforts to develop potent and selective PDK1 inhibitors with suitable drug like properties have been unsuccessful and no compounds have entered clinical development.
  • PDK1 inhibitors GSK2334470 and BX-320/-795 have shown moderate efficacy and thus, it has been proposed that PDK1 may not be rate limiting in promoting cancer cell growth. Alternatively, these inhibitors may simply have poor pharmacological properties, failing to achieve sufficient inhibition to produce an effect, or the type of cancers cells used did not depend on PDK1 for growth.
  • compositions comprising compounds that are stable and that allow for rapid dissolution and enhanced oral bioavailability. Furthermore, it is believed that the efficacy of these compounds correlates with drug exposure. Accordingly, it is desirable to be able to administer such compounds at the highest possible dose, i.e., the highest possible dose at which the side-effect profile is acceptable. A dosing regimen that achieves a higher exposure to the compounds thereby would provide a meaningful benefit in the treatment of patients suffering from cancer.
  • the present disclosure provides pharmaceutical compositions as described herein with superior properties, including rapid dissolution and increased oral bioavailability.
  • the present disclosure also provides processes for the preparation of said pharmaceutical compositions.
  • the present disclosure provides a formulation comprising 6-cyano-3-[4- (3-methylamino-lH-pyrazolo[3,4-b]pyridin-5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide (Formula 1): or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical formulation comprising a compound, a polymer carrier, a bioavailability enhancer and at least one excipient, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound to the polymer carrier weight ratio is from about 1 : 1 to about 1 :3;
  • the compound to the bioavailability enhancer weight ratio is from about 1 : 1 to about 5: 1;
  • the at least one excipient is selected from the group consisting of diluent, glidant, disintegrant, capsule shell, and lubricant.
  • the present disclosure provides a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), a bioavailability enhancer and at least one excipient, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound to the carrier weight ratio is from about 1 : 1 to about 1 :3;
  • the compound to the bioavailability enhancer weight ratio is from about 1 : 1 to about 5: 1;
  • the at least one excipient is selected from the group consisting of diluent, binder, filler, disintegrant, capsule shell, and lubricant.
  • a pharmaceutical formulation comprising a compound, a polymer carrier, and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of from about 90% w/w to about 95% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 40% w/w to about 95% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide of Formula (I)
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 90% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 80% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • a pharmaceutical formulation having an intra-granular component comprising:
  • the present disclosure provides pharmaceutical compositions comprising the formulation as described herein, wherein the compound modulates a PDK1- PIF mediated substrate interaction-dependent cancer survival pathway, such as an RSK2- dependent pathway, or an Akt-independent pathway, that is implicated in cancer growth and survival.
  • a PDK1- PIF mediated substrate interaction-dependent cancer survival pathway such as an RSK2- dependent pathway, or an Akt-independent pathway, that is implicated in cancer growth and survival.
  • the present disclosure provides methods for modulating a kinase activation pathway implicated in cancer growth and survival in a subject, comprising administering to the subject a pharmaceutical composition comprising the formulation as described herein.
  • Figures 1 A and IB depict the results of the non-sink dissolution of pharmaceutical compositions comprising the compound of Formula (I).
  • Figures 2A and 2B depict the results of scanning electronic microscopy (SEM) of pharmaceutical compositions comprising the compound of Formula (I).
  • Figure 3 depicts the X-ray diffraction patterns (XRPD) of pharmaceutical compositions comprising the compound of Formula (I).
  • Figure 4 depicts the results of the MDSC characterization of pharmaceutical compositions comprising the compound of Formula (I).
  • Figure 5 depicts the XRPD diffraction pattern of the compound of Formula (I) API.
  • Figure 6 depicts the results of melt-quench by DSC of the compound of Formula (I) API.
  • Figure 7 depicts the results of the SEM characterization of compound of Formula (I) API.
  • Figure 8 depicts the experimental design of the solvent shift assay.
  • Figure 9 depicts the results of the compound of Formula (I) API characterization (API: polymer solvent shift).
  • the present disclosure relates to formulations, which may modulate PDK1 activity and are accordingly useful in methods of treatment of the human or animal body.
  • the present disclosure also relates to their use in the treatment of disorders wherein PDK1 is implicated, such as cancer.
  • the present disclosure provides a formulation comprising 6-cyano-3-[4- (3-methylamino-lH-pyrazolo[3,4-b]pyridin-5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide (Formula 1): or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical formulation comprising a compound, a polymer carrier, a bioavailability enhancer and at least one excipient, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound to the polymer carrier weight ratio is from about 1 : 1 to about 1 :3;
  • the compound to the bioavailability enhancer weight ratio is from about 1 : 1 to about 5: 1;
  • the at least one excipient is selected from the group consisting of diluent, glidant, disintegrant, capsule shell, and lubricant.
  • the present disclosure provides a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), a bioavailability enhancer and at least one excipient, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound to the carrier weight ratio is from about 1 : 1 to about 1 :3;
  • the compound to the bioavailability enhancer weight ratio is from about 1 : 1 to about 5: 1;
  • the at least one excipient is selected from the group consisting of diluent, binder, filler, disintegrant, capsule shell, and lubricant.
  • the present disclosure provides, a pharmaceutical formulation comprising a compound, a polymer carrier, and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of from about 90% w/w to about 95% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the present disclosure provides, a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 90% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 80% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer in a weight ratio of about 3:6: 1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide of Formula (I)
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of from about 50% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation having an intra-granular component comprising:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, a carrier (e.g., a polymer or copolymer), or a bioavailability enhancer.
  • the present disclosure provides a pharmaceutical composition comprising Formula (I), a carrier (e.g., a polymer or copolymer), and a bioavailability enhancer.
  • a pharmaceutical composition comprising Formula (I), a carrier (e.g., a polymer or copolymer), or a bioavailability enhancer.
  • the copolymer is polyvinyl pyrrolidone, hydroxy propyl methylcellulose acetate succinate (HPMCAS-M), hydroxy propyl methylcellulose (HPMC), eudragit, CAP, or poly(l-vinylpyrrolidone-co-vinyl acetate).
  • the copolymer is polyvinyl pyrrolidone.
  • the copolymer is HPMCAS-M.
  • the copolymer is HPMC.
  • the copolymer is eudragit.
  • the copolymer is CAP.
  • the copolymer is poly(l-vinylpyrrolidone-co-vinyl acetate).
  • the compound to the polymer carrier weight ratio is about 1 : 1, about 1:2, or about 1 :3.
  • the compound to the polymer carrier weight ratio is about 1 : 1.
  • the compound to the polymer carrier weight ratio is about 1 :2.
  • the compound to the polymer carrier weight ratio is about 1 :3.
  • the compound to the bioavailability enhancer weight ratio is about 1 : 1, about 2: 1, about 3: 1, about 4: 1, or about 5: 1.
  • the compound to the bioavailability enhancer weight ratio is about 1 : 1.
  • the compound to the bioavailability enhancer weight ratio is about 2: 1.
  • the compound to the bioavailability enhancer weight ratio is about 3: 1.
  • the compound to the bioavailability enhancer weight ratio is about 4: 1.
  • the compound to the bioavailability enhancer weight ratio is about 5: 1.
  • the at least one excipient is selected from the group consisting of diluent, binder/filler, glidant, disintegrant, capsule shell, and lubricant.
  • the at least one excipient is a diluent.
  • the at least one excipient is a glidant. [0064] In some embodiments, the at least one excipient is a disintegrant.
  • the at least one excipient is a capsule shell.
  • the at least one excipient is a lubricant.
  • the at least one excipient is a binder/filler.
  • the compound is present in an amount from about 5% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 10% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 15% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 20% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 25% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 30% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 35% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 40% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 45% w/w to about 50% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 45% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 40% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 35% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 30% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 25% w/w of the pharmaceutical formulation. [0082] In some embodiments, the compound is present in an amount from about 5% w/w to about 20% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 15% w/w of the pharmaceutical formulation.
  • the compound is present in an amount from about 5% w/w to about 10% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 5% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 10% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 15% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 20% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 25% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 30% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 35% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 40% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 45% w/w of the pharmaceutical formulation.
  • the compound is present in an amount of about 50% w/w of the pharmaceutical formulation.
  • the formulation has a dissolution rate of at least about 10% at about 30 min.
  • the formulation has a dissolution rate of at least about 15% at about 30 min.
  • the formulation has a dissolution rate of at least about 20% at about 30 min. [0098] In some embodiments, the formulation has a dissolution rate of at least about 25% at about 30 min.
  • the formulation has a dissolution rate of at least about 30% at about 30 min.
  • the formulation has a dissolution rate of at least about 35% at about 30 min.
  • the formulation has a dissolution rate of at least about 40% at about 30 min.
  • the formulation has a dissolution rate of at least about 45% at about 30 min.
  • the formulation has a dissolution rate of at least about 50% at about 30 min.
  • the formulation has a dissolution rate of at least about 55% at about 30 min.
  • the formulation has a dissolution rate of at least about 60% at about 30 min.
  • the formulation has a dissolution rate of at least about 65% at about 30 min.
  • the formulation has a dissolution rate of at least about 70% at about 30 min.
  • the formulation has a dissolution rate of at least about 75% at about 30 min.
  • the formulation has a dissolution rate of at least about 80% at about 30 min.
  • the formulation has a dissolution rate of at least about 10% at about one hour.
  • the formulation has a dissolution rate of at least about 15% at about one hour.
  • the formulation has a dissolution rate of at least about 20% at about one hour.
  • the formulation has a dissolution rate of at least about 25% at about one hour. [0114] In some embodiments, the formulation has a dissolution rate of at least about 30% at about one hour.
  • the formulation has a dissolution rate of at least about 35% at about one hour.
  • the formulation has a dissolution rate of at least about 40% at about one hour.
  • the formulation has a dissolution rate of at least about 45% at about one hour.
  • the formulation has a dissolution rate of at least about 50% at about one hour.
  • the formulation has a dissolution rate of at least about 55% at about one hour.
  • the formulation has a dissolution rate of at least about 60% at about one hour.
  • the formulation has a dissolution rate of at least about 65% at about one hour.
  • the formulation has a dissolution rate of at least about 70% at about one hour.
  • the formulation has a dissolution rate of at least about 75% at about one hour.
  • the formulation has a dissolution rate of at least about 80% at about one hour.
  • the formulation has a dissolution rate of at least about 85% at about one hour.
  • the formulation has a dissolution rate of at least about 90% at about one hour.
  • the formulation has a dissolution rate of at least about 95% at about one hour.
  • the formulation has a dissolution rate of at least about 100% at about one hour.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 95% w/w of the pharmaceutical formulation. [0130] In some embodiments, the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 90% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 85% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 80% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 75% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 70% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 65% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 60% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 55% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 54% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 50% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 40% w/w of the pharmaceutical formulation. [0141] In some embodiments, the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 35% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 30% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 25% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 20% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 90% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 80% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 70% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 60% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 50% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 40% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 30% w/w of the pharmaceutical formulation. [0152] In some embodiments, the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 20% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 10% w/w of the pharmaceutical formulation.
  • the compound to the polymer carrier weight ratio is about 1 :2 and the compound to the bioavailability enhancer weight ratio is about 3: 1.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 95% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 90% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 85% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 80% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 75% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 70% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 65% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 60% w/w of the pharmaceutical formulation.
  • the compound, the carrier and the bioavailability enhancer are collectively present in an amount of about 55% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 50% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 45% w/w of the pharmaceutical formulation. [0166] In some embodiments, the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 40% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 35% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 30% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 25% w/w of the pharmaceutical formulation.
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 20% w/w of the pharmaceutical formulation.
  • the at least one excipient is not a solubilizer or a plasticizer.
  • the at least one excipient is not a solubilizer.
  • the at least one excipient is not a plasticizer.
  • the formulation is free from solubilizers.
  • the formulation is free from plasticizers.
  • the formulation is free from polyethylene glycol (PEG).
  • the formulation is free from polyethylene glycol 1500 (PEG 1500).
  • the polymer carrier is selected from the group consisting of: vinylpyrrolidone-vinyl acetate copolymer, hydroxy propyl methylcellulose (HPMC), hydroxy propyl methylcellulose acetate succinate copolymer, and polyvinylpyrrolidone.
  • the polymer carrier is vinylpyrrolidone-vinyl acetate copolymer.
  • the polymer carrier is hydroxy propyl methylcellulose.
  • the polymer carrier is hydroxy propyl methylcellulose acetate succinate copolymer.
  • the polymer carrier is polyvinylpyrrolidone.
  • the carrier is a polymer. [0184] In some embodiments, the carrier is a copolymer.
  • the bioavailability enhancer is selected from the group consisting of: d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and cholecalciferol polyethylene glycol succinate (CPGS).
  • TPGS d-a-tocopheryl polyethylene glycol 1000 succinate
  • CPGS cholecalciferol polyethylene glycol succinate
  • the bioavailability enhancer is d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS).
  • the bioavailability enhancer is cholecalciferol polyethylene glycol succinate (CPGS).
  • the at least one excipient is mannitol.
  • the at least one excipient is not mannitol.
  • the formulation is free from sugars.
  • the at least one excipient is croscarmellose.
  • the at least one excipient is microcrystalline cellulose.
  • the at least one excipient is magnesium stearate.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 2% w/w of the pharmaceutical formulation. [0195] In some embodiments, the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 3% w/w of the pharmaceutical formulation. [0196] In some embodiments, the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 4% w/w of the pharmaceutical formulation. [0197] In some embodiments, the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 5% w/w of the pharmaceutical formulation. [0198] In some embodiments, the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 6% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 7% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 8% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 9% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 10% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 11% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises croscarmellose sodium in an amount of about 12% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises magnesium stearate in an amount from about 1% w/w to about 10% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises magnesium stearate in an amount of about 1% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises magnesium stearate in an amount of about 3% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell from an amount of about 5% w/w to about 25% w/w of the pharmaceutical formulation. [0209] In some embodiments, the pharmaceutical formulation further comprises a capsule shell in an amount of about 5% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell in an amount of about 9% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell in an amount of about 10% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell in an amount of about 15% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell in an amount of about 17% w/w of the pharmaceutical formulation.
  • the pharmaceutical formulation further comprises a capsule shell in an amount of about 20% w/w of the pharmaceutical formulation.
  • the capsule shell is a gelatin capsule shell.
  • the capsule shell is a HPMC capsule shell.
  • the polymer carrier is vinylpyrrolidone-vinyl acetate copolymer and the bioavailability enhancer is d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS).
  • TPGS d-a-tocopheryl polyethylene glycol 1000 succinate
  • the pharmaceutical formulation is one of the formulations provided in Table 1.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the croscarmellose is absent and sodium starch glycolate is present.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 30% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 40% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 50% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 60% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 70% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 80% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 90% w/w of the pharmaceutical formulation.
  • the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 95% w/w of the pharmaceutical formulation.
  • the present disclosure provides, a method of treating or preventing a disease or disorder, comprising administering to a subject in need thereof a formulation as described herein.
  • the present disclosure provides, a method of treating a disease or disorder, comprising administering to a subject in need thereof a formulation as described herein.
  • the present disclosure provides, a formulation as described herein for use in treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides, a formulation as described herein for use in treating a disease or disorder in a subject in need thereof.
  • the present disclosure provides, a formulation as described herein for treating or preventing a disease or disorder in a subject in need thereof.
  • the present disclosure provides, a formulation as described herein for treating a disease or disorder in a subject in need thereof.
  • the present disclosure provides, use of a formulation as described herein, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.
  • the present disclosure provides, use of a formulation as described herein, in the manufacture of a medicament for the treatment of a disease or disorder in a subject in need thereof.
  • the disease or disorder can be ameliorated by inhibition ofPDKl.
  • the disease or disorder can be ameliorated by inhibition ofPDKl and PI3K.
  • the PI3K is PI3Ka.
  • the disease or disorder is a cancer.
  • the cancer is a hematologic cancer.
  • the hematologic cancer selected from the group consisting of leukemias, lymphomas, and myelomas.
  • the hematologic cancer is selected from anaplastic large-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, B-cell lymphoma, T- cell lymphoma, mantle cell lymphoma, histiocytic lymphoma, T-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic myelogenous leukemia, acute lymphocytic (lymphoblastic) leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, and plasma cell leukemia.
  • the hematologic cancer is anaplastic large-cell lymphoma.
  • the hematologic cancer is non-Hodgkin’s lymphoma.
  • the hematologic cancer is Hodgkin’s lymphoma.
  • the hematologic cancer is B-cell lymphoma.
  • the hematologic cancer is T-cell lymphoma.
  • the hematologic cancer is mantle cell lymphoma.
  • the hematologic cancer is histiocytic lymphoma.
  • the hematologic cancer is T-cell leukemia.
  • the hematologic cancer is chronic lymphocytic leukemia.
  • the hematologic cancer is multiple myeloma.
  • the hematologic cancer is chronic myelogenous leukemia.
  • the hematologic cancer is acute lymphocytic (lymphoblastic) leukemia.
  • the hematologic cancer is acute myelogenous leukemia.
  • the hematologic cancer is acute myeloblastic leukemia.
  • the hematologic cancer is plasma cell leukemia.
  • the cancer is a solid tumor.
  • the cancer is a breast cancer.
  • the subject is a human.
  • the formulation described herein may be used to modulate the growth, proliferation, or survival of cancer cells in which PDK1-PIF- mediated substrate interaction-dependent cell survival pathways are implicated.
  • the present disclosure provides a method of treating cancer in a subject in need thereof by inducing cancer cell apoptosis through inhibition of PDK1-PIF mediated substrate interaction-dependent cancer survival pathways, comprising administering to said subject a formulation as described herein.
  • the disclosure provides a method of treating cancer in a subject in need thereof by inhibiting PDK1-PIF mediated substrate interaction-dependent cancer cell growth, proliferation, or survival, comprising administering to said subject a formulation as described herein.
  • the present disclosure provides a method of preparing a medicament for use in the treatment of cancer in which the growth, proliferation, or survival of the cancer is dependent on a PDKl-PIF-mediated substrate interaction, comprising a therapeutically effective amount of a formulation as described herein.
  • the present disclosure provides a product comprising a container and a medicament for use in the treatment of cancer in which the growth, proliferation, or survival of the cancer is dependent on a PDKl-PIF-mediated substrate interaction, in which the medicament comprises a formulation as described herein.
  • the present disclosure provides a method of treating cancer in a subject in need thereof by inducing cancer cell apoptosis through inhibition of RSK2- dependent survival pathways, comprising administering to said subject a formulation as described herein.
  • the present disclosure provides a method of treating cancer in a subject in need thereof by inhibiting RSK2-dependent cancer cell growth, proliferation, or survival, comprising administering to said subject a formulation described herein.
  • the present disclosure provides a use of a formulation as described herein for the preparation of a medicament for the treatment of cancer in which PDK1-PIF- mediated substrate interaction-dependent cell survival pathways are implicated.
  • the present disclosure provides a use of a formulation as described herein for the preparation of a medicament for the treatment of cancer in which RSK2- dependent cell survival pathways are implicated.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • one enantiomer may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2J/-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N- substituted pyrrolidinyl).
  • an effective amount means an amount of a therapeutic substance ⁇ e.g., a composition of the invention) that is (1) sufficient upon appropriate administration to a patient (a) to cause a detectable decrease in the severity of the disorder or disease state being treated; (b) to ameliorate or alleviate the patient's symptoms of the disease or disorder; or (c) to slow or prevent advancement of: or otherwise stabilize or prolong stabilization of, the disorder or disease state being treated (e. g., prevent additional tumor growth of a cancer); and (2) equal to or less than the maximum tolerated dose (MTD).
  • the clinically effective amount can be expressed as amount of therapeutic substance per patient BSA, e.g., as mg/m2.
  • subject means a mammal (e.g., human) being diagnosed with, exhibiting symptoms of or otherwise believed to be afflicted with or suffering from a disease, disorder, or condition.
  • subject means a mammal (e.g., human) being diagnosed with, exhibiting symptoms of or otherwise believed to be afflicted with or suffering from a disease, disorder, or condition.
  • an “active moiety” means the molecule or ion, excluding those appended portions of the molecule that cause a compound to be a salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule.
  • the active moiety is responsible for the physiological or pharmacological action of the drug substance without regard to the actual charged state of the molecule in vivo.
  • the active moiety of a hydrochloride salt of a base is the free base and not the protonated form of the base.
  • the active moiety of a metal salt of an acid is the free acid.
  • an active ingredient When an active ingredient occurs as a salt, the ingredient will be expressed, unless otherwise indicated, using the name of the active moiety and not the name of the salt (e.g., “Compound A” rather than “Compound A hydrochloride”).
  • the strength of a pharmaceutical product will also be expressed in terms of the active moiety (e.g., “100 mg Compound A”) rather than the salt strength equivalent (i.e., “123.7 mg Compound A hydrochloride”).
  • a dose to be administered to a patient will be expressed in terms of the active moiety rather than the salt.
  • a unit dose too, will be expressed in terms of the active moiety rather than the salt.
  • an amount of an active ingredient in a solid dispersion extrudate of the invention when indicated, the amount will be understood as an amount of the physical form employed, which may be a salt or other derivative. In general, processes of manufacture will reference the active ingredient rather than the active moiety.
  • an amount identified in a pharmaceutical product incorporating a pharmaceutical composition comprising a solid dispersion extrudate of a compound and one or more other excipients
  • an amount indicated for use in a method of treatment will be understood as an amount of the active moiety.
  • compounds as described herein are useful for the treatment of one or more diseases, disorders, and/or conditions that may be alleviated by inhibiting (i.e. decreasing) certain PDK1 activities, including Pl-independent PIF pocket substrate binding and PDK1-PIF mediated substrate interaction-dependent cell growth, proliferation, or survival.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • provided methods include administering to the subject a formulation.
  • a cancer treated in accordance with the present invention is, by way of nonlimiting example, glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g., small-cell lung carcinoma, non-small-cell lung carcinoma), gastric carcinoma, cervical carcinoma, melanoma, skin carcinoma, colorectal carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, anaplastic large-cell lymphoma, leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, colon cancer (e.g. microsatellite instability-high colorectal cancer).
  • lung cancer e.g., small-cell lung carcinoma, non-small-cell lung carcinoma
  • gastric carcinoma cervical carcinoma
  • melanoma skin carcinoma
  • colorectal carcinoma
  • the present invention provides methods of treating cancers that are hematologic cancers.
  • provided methods include administering to the subject a therapeutically effective amount of a provided compound.
  • hematologic cancer includes blood-borne tumors and diseases or disorders involving abnormal cell growth and/or proliferation in tissues of hematopoietic origin, such as lymphomas, leukemias, and myelomas.
  • Hematologic cancers that may be treated according to the invention include, by way of nonlimiting example, anaplastic large-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, B-cell lymphoma (e.g., ABC-diffuse large B-cell lymphoma, GCB- diffuse large B-cell lymphoma), T-cell lymphoma, mantle cell lymphoma, histiocytic lymphoma, T-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic myeloid leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia, plasma cell leukemia.
  • B-cell lymphoma e.g., ABC-diffuse large B-cell lymphoma, GCB- diffuse large B-cell lymphoma
  • T-cell lymphoma mantle cell lympho
  • precancerous condition means a condition, abnormal tissue growth, or lesion that tends or is likely to become cancerous.
  • Precancerous conditions include, for example, actinic keratosis, adenomatous polyps of the colon, cervical dysplasia, and antecedent hematological disorders such as myelofibrosis, aplastic anemia, paroxysmal nocturnal hemoglobinuria, polycythemia vera, and myelodysplastic syndrome.
  • candidate inhibitors capable of decreasing PDK1-P IF -mediated substrate interaction-dependent cell survival pathways may be identified in vitro.
  • the activity of provided compounds can be assayed utilizing methods known in the art, such as, for example, those methods presented in international patent applications WO 2008/005457 A2, WO 2011/044157 Al, and WO 2017/070565 Al.
  • Compounds that decrease PDK1-PIF -mediated substrate interaction-dependent cell survival pathways may be identified and tested using biologically active PDK1 and other elements of these pathways, either recombinant or naturally-occurring.
  • PDK1, RSK2, and Akt for example, can be found in native cells, isolated in vitro, or co-expressed or expressed in a cell.
  • Measuring the reduction in the PDK1-P IF -mediated substrate interaction-dependent cell survival pathways in the presence of an inhibitor relative to the activity in the absence of the inhibitor may be performed using a variety of methods known in the art, such as in the assays described herein. Other methods for assaying the activity of elements of PDK1-PIF- mediated substrate interaction-dependent cell survival pathways are known in the art. The selection of appropriate assay methods is well within the capabilities of those of skill in the art.
  • Compounds may be further tested in cell models or animal models for their ability to cause a detectable change in phenotype related to PDK1-PIF -mediated substrate interactiondependent cell survival pathways.
  • animal models may be used to test inhibitors of PDK1 for their ability to treat cancer in an animal model.
  • Compounds may be further tested for their ability to selectively inhibit or induce expression of genes or proteins that could serve as biomarkers to monitor inhibition of PDK1 activity in animal models or in healthy subjects or in patients.
  • the present invention provides pharmaceutical compositions comprising a compound, optionally in combination with a pharmaceutically acceptable excipient (e.g., a carrier).
  • a pharmaceutically acceptable excipient e.g., a carrier
  • compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the compounds disclosed herein.
  • pharmaceutical compositions include a pharmaceutically acceptable salt.
  • a compound included in the pharmaceutical composition may be covalently attached to a pharmaceutically acceptable carrier.
  • the inventive compound included in the pharmaceutical composition is not covalently linked to a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier,” as used herein refers to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the compounds used in accordance with the provided methods.
  • Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which do not deleteriously react with the compounds used in accordance with the provided methods.
  • substantially amorphous refers to a solid material having little or no long range order in the position of its molecules.
  • a substantially amorphous material has less than about 30% crystallinity (e.g., less than about 25% crystallinity, less than about 20% crystallinity, less than about 15% crystallinity, less than about 10% crystallinity, less than about 5% crystallinity, less than about 4% crystallinity).
  • crystallinity e.g., less than about 25% crystallinity, less than about 20% crystallinity, less than about 15% crystallinity, less than about 10% crystallinity, less than about 5% crystallinity, less than about 4% crystallinity.
  • 'substantially amorphous' materials include 'amorphous' materials, which refers to materials having no (0%) observable crystallinity.
  • crystalline and related terms used herein, when used to describe a substance, component or product is substantially crystalline, as determined by X- ray diffraction, polarized optical microscopy and/or FT-Ram an microscopy.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt of a compound that, upon administration to a recipient, is capable of providing, either directly or indirectly, that compound or an active metabolite or residue thereof.
  • compositions 1, 2, or 3 include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(Ci-4alkyl)4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of a compound. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • compositions solid dispersion extrudate is substantially amorphous.
  • the substantially amorphous pharmaceutical composition comprises an amount of crystalline compound, or a pharmaceutically acceptable salt thereof.
  • the amount of crystalline compound is less than about 30%, less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 4%.
  • the substantially amorphous character of a solid dispersion extrudate can be detected using analytical methods, including but not limited to, microscopic methods (scanning electronic microscopy (SEM), polarized light microscopy (PLM), hot stage microscopy (HSM), thermal methods (differential scanning calorimetry (DSC) modulated DSC (rnDSC), X-ray diffraction methods (XRPD). and spectroscopic methods (FT-Infrared (IR), FT-Raman, solid state NMR (ssNMR), and confocal Raman microscopy (CRM).
  • the amorphous character of a pharmaceutical composition is detected by X-ray powder diffraction (XRPD).
  • the amount of crystalline substance in a substantially amorphous pharmaceutical composition can be determined using a calibration curve based on samples of variable crystalline content (high and low regions).
  • the amount of crystalline compound in a substantially amorphous solid dispersion extrudcate of the invention may affect the solubility of the composition.
  • the amount of crystalline compound in a substantially amorphous solid dispersion extrudate of the invention may affect the bioavailability of the composition. In one aspect, less than about 30% of crystalline compound in a substantially amorphous solid dispersion extrudate does not reduce the solubility and/or bioavailability of the composition.
  • less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than about 24%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4% of crystalline compound in a substantially amorphous solid dispersion extrudate does not significantly reduce the solubility and/or bioavailability of the composition.
  • the solid dispersion extrudate materials of the invention include a polymer carrier.
  • the polymer carrier may be any substance that is suitable for use in hot melt extrusion processes described herein and compatible with the compounds as described herein.
  • the polymer carrier may be a vinylpyrrolidone-vinyl acetate copolymer.
  • a vinylpyrrolidone-vinyl acetate copolymer is a copovidone.
  • Copovidone materials are available commercially, such as the Kollidon® polymers from (Bayer), including, for example, Kollidon® VA64 (CAS 25086-89-9). Other copovidione materials that are freely water soluble may be used.
  • useful copovidone materials may be copolymers of 6 parts of A-vinylpyrrolidone and 4 parts of vinyl acetate. Such materials may have a molecular weight of about 45,000 g/mol. Materials with physicochemical properties similar to those of such copovidone materials (e.g., plasticity, solubilization, etc.) may be used as polymer carriers according to the invention. Blends of such materials may be used as the polymer carrier component of these extrudates.
  • the solid dispersion extrudate materials of the invention include a solubilizer.
  • the solubilizer may be any substance that is suitable for use in hot melt extrusion processes describe herein and compatible with the compounds as described herein.
  • the solubilizer may be a polyethylene glycol 1500 (PEG 1500; CAS 25322-68-3). Materials with physicochemical properties similar to those of such PEG 1500 materials may be used as solubilizers according to the invention. Blends of such materials may be used as the solubilizer component of these extrudates.
  • the solid dispersion extrudate materials of the invention include a bioavailability enhancer.
  • the bioavailability enhancer may be any substance that is suitable for use in hot melt extrusion processes describe herein and compatible with the compounds as described herein.
  • the bioavailability enhancer may be d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), an ester of esterification of the acid crystalline d-a-tocopheryl acid succinate with polyethylene glycol 1000, e.g., vitamin E TPGS NF (Eastman).
  • TPGS polyethylene glycol 1000 succinate
  • an ester of esterification of the acid crystalline d-a-tocopheryl acid succinate with polyethylene glycol 1000 e.g., vitamin E TPGS NF (Eastman).
  • Materials with physicochemical properties similar to those of such TPGS materials may be used as bioavailability enhancers according to the invention. Blends of such materials may be used as the bioavailability enhancer component of these
  • the solid dispersion extrudates of the invention may be made as needed to satisfy particular pharmaceutical needs, adjusting the relative amounts of the compound, polymer carrier, solubilizer, and bioavailability enhancer.
  • the compound in the solid dispersion extrudates useful in the pharmaceutical compositions of the invention may be provided in amounts of about 1% w/w to about 50%, about 2% to about 40%, about 5% to about 35%, about 10% to about 30%, about 10% to about 20%, about 10% to about 15%, or about 15% to about 25% w/w.
  • the compound can be about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% w/w in the solid dispersion extrudate.
  • the amount of the compound should not substantially degrade the physically properties of the overall extrudate feed material for the hot melt process.
  • the polymer carrier may be provided in amounts of about 40% to about 80%, about 45% to about 75%, about 50% to about 70%, about 60% to about 80%, or about 40% to about 60% w/w.
  • the polymer carrier can be about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% w/w in the solid dispersion extrudate.
  • the solubilizer may be provided in amounts of about 1% to about 20%, about 5% to about 15%, about 7.5% to about 12.5%, or about 10% to about 20% w/w.
  • the solubilizer can be about 5%, about 7.5%, about 10%, about 12.5%, about 15%, or about 20% w/w in the solid dispersion extrudate.
  • the bioavailability enhancer may be provided in amounts of about 1% to about 20%, about 5% to about 15%, about 7.5% to about 12.5%, or about 10% to about 20% w/w.
  • the solubilizer can be about 5%, about 7.5%, about 10%, about 12.5%, about 15%, or about 20% w/w in the solid dispersion extrudate.
  • the pharmaceutical composition comprises a solid dispersion extrudate that is substantially amorphous. In some embodiments, the pharmaceutical composition comprises a solid dispersion extrudate that is amorphous. Determination of the solid state of the solid dispersion extrudate, such as determination whether the extrudate is substantially amorphous, or amorphous, may be assessed using methods available in the art, such as x-ray powder diffraction (XRPD) analysis or optical microscopy.
  • XRPD x-ray powder diffraction
  • the pharmaceutical composition comprises a solid dispersion extrudate that contains no microcrystalline domains of the compound. In some embodiments, the pharmaceutical composition comprises a solid dispersion extrudate that contains microcrystalline domains of the compound. Existence of crystalline domains in the extrudate may be assessed using methods available in the art, such as Raman spectroscopy analysis and micro-Raman spectroscopy analysis.
  • the hot melt process is a process of increasing importance in the pharmaceutical industry, as it can enable the use, as active pharmaceutical ingredients (API), of compounds that have physicochemical properties that might otherwise limit their use in pharmaceutical applications.
  • API active pharmaceutical ingredients
  • Prime among these properties is solubility, where low solubility of a compound can profoundly limit its bioavailability in a patient, impairing its therapeutic utility and perhaps even precluding use of the compound in the clinic.
  • solubility limitations is an important focus of pharmaceutical development.
  • Hot melt extrusion method One method that has been used to improve the bioavailability of some compounds is the hot melt extrusion method.
  • a general overview of this method is given, for example, in K. Kolter, M. Karl, and A. Gryczke, Hot-Melt Extrusion with BASF Pharma Polymers, Extrusion Compendium, 2 nd Revised and Enlarged Edition, BASF SE, October 2012 (ISBN 978-3-00-039415-7). See also, e.g., Crowley et al., Drug Devel and Industrial Pharmacy, 2007, 33:909-926, Lang et al., Drug Devel and Industrial Pharmacy, 2014, 40(9): 1122-1155, and Madan et al., Asian J. Pharm.
  • the process involves providing feedstocks of a polymeric material (usually amorphous) and the compound of interest (often crystalline) to a device that can mix and apply shear stress to the two feed materials to provide a mixture, heating the mixed material, and pressing or extruding the mixed materials, to yield a substantially amorphous dispersion of the compound of interest in the polymer carrier.
  • a polymeric material usually amorphous
  • the compound of interest often crystalline
  • Preparation of the solid dispersion extrudates of the invention can be conducted at temperatures suitable for the materials constituting the composition of the dispersion, particularly to avoid undesirable physical degradation of the compound or of the components of the composition.
  • the extruding is carried out in an extruder operating with a melt temperature ranging about 95 °C to about 160 °C.
  • the hot melt process may be conducted at melt temperatures in the range of about 130 °C to about 160 °C, about 140 °C to about 150 °C, about 140 °C, about 145 °C, or about 150 °C.
  • the extruding may be carried out in an extruder operating with a barrel temperature comprising stages ranging about 35 °C to about 160 °C.
  • Suitable hot melt procedures may be used on hot melt extrusion apparatus commercially available to the skilled person.
  • the compound may be combined with the polymer carrier, solubilizer, and bioavailability enhancer, and fed together to the extrusion apparatus. Or the compound may be provided as a separate feed from the polymeric materials.
  • the feed materials may be extruded using a co-rotating twin screw extruder. Recirculation time may be about 5 minutes to about 15 minutes, for example about 10 minutes.
  • the extrudate may then be chopped or milled into fine particles or pellets upon extrusion.
  • Suitable spray drying procedures may be used according to commercially known methods to the skilled person.
  • the compound may be combined with the carrier, solubilizer, or bioavailability enhancer.
  • the spray dryer technique is in a closed or open loop system.
  • the type of atomiser or nozzle used is a pressure, two-fluid, ultrasonic or rotary atomizer or nozzle.
  • the powder recovery system used is a cyclone and/or a filter bag. Spray drying process may be used for compounds that have physicochemical properties which might otherwise limit their use in pharmaceutical applications.
  • the present invention also provides pharmaceutical compositions comprising one or more provided compounds in the form of a solid dispersion extrudate, and one or more pharmaceutically acceptable carriers or excipients.
  • compositions described herein are administered by inhalation, for example, intranasally.
  • compositions are administered transdermally. It is also envisioned that multiple routes of administration can be used to administer the compounds using compositions of the invention.
  • the solid dispersion extrudate in the pharmaceutical compositions will be provided as a powder or particulate material of preferred dimension and handling characteristics, depending on the intended composition type and the method of administration of the composition.
  • the solid dispersion extrudate is subjected to a step of comminution or milling by conventional means, which produces a comminuted or milled extrudate material, with the appearance of a powder, particulate, or pellet material.
  • This powder, particulate, or pellet material can then be formulated into pharmaceutical compositions with one or more pharmaceutically acceptable excipients as described herein.
  • pharmaceutically acceptable excipients can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier is one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier when the composition is a powder or particulate, is a finely divided solid in a mixture with the finely divided active component. In some embodiments, when the composition is formulated for a tablet, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • tablets, powders, capsules, pills, cachets, and/or lozenges are used as solid dosage forms suitable for oral administration.
  • provided powders, capsules, and tablets contain from 5% to 70% of the compound.
  • Suitable pharmaceutically acceptable excipients may be selected from known GRAS ingredients, including, for example, magnesium carbonate, magnesium stearate, talc, sugars (such as glucose, lactose), pectins, dextrins, starches, gelatins, gums (such as tragacanth), celluloses (such as methylcellulose, sodium carboxymethylcellulose), low melting waxes, cocoa butter, and the like.
  • Microcrystalline cellulose for example, can be used to improve powder flow characteristics for capsule filling or tablet compression.
  • the pharmaceutical composition is in the form of a capsule.
  • Pharmaceutically acceptable capsules of various types are known in the art.
  • capsules of hydroxypropyl methylcellulose or gelatin may be used.
  • Capsules are desirably suitable for oral administration to patients.
  • capsules may be size 00 or size 1.
  • Orally administrable forms of the product can be formulated as needed to provide a desired amount of the active moiety of the included compound.
  • such forms as capsules or tablets may be formulated to contain about 1 mg to about 1,000 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, or about 5 mg to about 200 mg of the active moiety.
  • such forms as capsules or tablets may be formulated to deliver about 1 mg to about 1,000 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, or about 5 mg to about 200 mg of the active moiety when administered to a patient.
  • the orally administrable form may provide a dose of about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, or about 1,000 mg of the active moiety.
  • Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, each of which is hereby incorporated by reference.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • liquid form preparations intended for conversion shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • provided pharmaceutical compositions are in unit dosage form.
  • the composition is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of a pharmaceutical composition, such as packeted tablets, capsules, and powders.
  • the unit dosage form is a capsule, tablet, cachet, or lozenge itself, or it is the appropriate number of any of these in packaged form.
  • the quantity of compound in a unit dosage form may be varied or adjusted from 0.1 mg to 10,000 mg, more typically 1.0 mg to 2,000 mg, most typically 10 mg to 1,000 mg, according to the particular application and the potency of the active component.
  • the unit dosage may be about 5 mg to about 500 mg, about 5 mg to about 400 mg, or about 5 mg to about 200 mg of the compound.
  • provided compositions contain other compatible therapeutic agents at doses calculated to be effective for a given purpose.
  • compositions according to the invention include compositions in which the compound is provided in a therapeutically effective amount, or in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • the compositions when administered in methods to treat cancer, will contain an amount of compound effective to achieve the desired result (e.g. decreasing the number of cancer cells in a subject).
  • the dosage and frequency (single or multiple doses) of administered to a mammal can vary depending upon a variety of factors, including a disease that results in increased activity of PDK1-PIF -mediated substrate interaction-dependent cell survival pathways, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., cancer), kind of concurrent treatment, complications from the disease being treated or other health-related problems.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • a therapeutically effective amount of the compound may be initially assessed using cell culture assays.
  • Target concentrations will be those concentrations of compound(s) that can reduce the activity of PDK1-PIF -mediated substrate interaction-dependent cell survival pathways, as measured, for example, using the methods described in the art.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring PDK1 inhibition and adjusting the dosage upwards or downwards, as described above.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient is sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects.
  • treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the dosage range is 0.001% to 10% w/v. In another embodiment, the dosage range is 0.1% to 5% w/v.
  • an effective amount of a pharmaceutical composition as described herein may be administered to the patient according to an intermittent dosing regimen, in which the dosing regimen comprises administering the composition once or twice weekly and the amount of the composition administered each week is about 1 mg to about 1,000 mg.
  • an effective amount of a pharmaceutical composition as described herein may be administered to the patient according to an intermittent dosing regimen, in which the dosing regimen comprises administering the composition once or twice weekly and the amount of the composition administered each week is about 5 mg to about 500 mg, about 5 mg to about 400 mg, or about 5 mg to about 200 mg.
  • the pharmaceutical composition may be administered in doses of about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg, or a range between any of the preceding values, for example, between about 10 mg and about 40 mg, between about 100 mg and about 125 mg, between about 50 mg and about 400 mg, or the like.
  • Formulations of compounds as described herein can be administered alone, or can be coadministered to a patient along with one or more other pharmaceutically active agents. Coadministration is meant to include simultaneous or sequential administration of such compounds individually or in combination (more than one compound).
  • the present disclosure provides methods comprising administering a formulation as described herein or pharmaceutical compositions provided herein in combination with one or more second active agents, and/or in combination with radiation therapy or surgery.
  • the present disclosure provides a pharmaceutical composition for use in a combinational therapy of treating cancer in a subject, comprising a formulation including a solid dispersion extrudate comprising a compound as described herein and a pharmaceutically acceptable carrier, in which the combinational therapy further comprises an effective amount of a second anti-cancer agent.
  • the present disclosure also encompasses therapies in which a subject may be administered a combination of a formulation comprising a compound as described herein and a second anti-cancer agent.
  • a combinational therapy it is possible to administer amounts of each of the agents in the combination that are sub -therapeutic if such agents were to be administered alone, but that in combination the agents act in an additive or supraadditive manner to be therapeutically effective.
  • Combinations designed, selected and/or optimised by methods described above, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the combination can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the combinations described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [0343] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the combinations of the present disclosure.
  • in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • Exemplary Embodiment 1 A pharmaceutical formulation comprising a compound, a polymer carrier, a bioavailability enhancer and at least one excipient, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide
  • the compound to the polymer carrier weight ratio is from about 1 : 1 to about 1 :3;
  • the compound to the bioavailability enhancer weight ratio is from about 1 : 1 to about 5: 1;
  • the at least one excipient is selected from the group consisting of diluent, glidant, disintegrant, capsule shell, and lubricant.
  • Exemplary Embodiment 2 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the compound to the polymer carrier weight ratio is about 1 : 1, about 1 :2, or about 1 :3.
  • Exemplary Embodiment 3 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the compound to the bioavailability enhancer weight ratio is about 1 : 1, about 2: 1, about 3: 1, about 4: 1, or about 5: 1.
  • Exemplary Embodiment 4 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the compound is present in an amount from about 5% w/w to about 50% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 5 The pharmaceutical formulation of Exemplary Embodiment 4, wherein the formulation has a dissolution rate of at least about 20% at about 30 min.
  • Exemplary Embodiment 6 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of less than about 95% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 7 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 95% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 8 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 90% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 9 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 85% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 10 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 80% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 11 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 75% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 12 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 70% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 13 The pharmaceutical formulation of Exemplary Embodiment 6, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 65% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 14 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the compound to the polymer carrier weight ratio is about 1 :2 and the compound to the bioavailability enhancer weight ratio is about 3: 1.
  • Exemplary Embodiment 15 The pharmaceutical formulation of Exemplary Embodiment 14, wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 35% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 16 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the at least one excipient is not a solubilizer or a plasticizer.
  • Exemplary Embodiment 17 The pharmaceutical formulation of Exemplary Embodiment 1, being free from solubilizers.
  • Exemplary Embodiment 18 The pharmaceutical formulation of Exemplary Embodiment 1, being free from plasticizers.
  • Exemplary Embodiment 19 The pharmaceutical formulation of Exemplary Embodiment 1, being free from polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Exemplary Embodiment 20 The pharmaceutical formulation of Exemplary Embodiment 1, being free from polyethylene glycol 1500 (PEG 1500).
  • Exemplary Embodiment 21 The pharmaceutical formulation of Exemplary
  • Embodiment 1 wherein the polymer carrier is selected from the group consisting of: vinylpyrrolidone-vinyl acetate copolymer, hydroxy propyl methylcellulose, hydroxy propyl methylcellulose acetate succinate copolymer, and polyvinylpyrrolidone.
  • the polymer carrier is selected from the group consisting of: vinylpyrrolidone-vinyl acetate copolymer, hydroxy propyl methylcellulose, hydroxy propyl methylcellulose acetate succinate copolymer, and polyvinylpyrrolidone.
  • Embodiment 1 wherein the bioavailability enhancer is selected from the group consisting of: d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) and cholecalciferol polyethylene glycol succinate (CPGS).
  • TPGS d-a-tocopheryl polyethylene glycol 1000 succinate
  • CPGS cholecalciferol polyethylene glycol succinate
  • Exemplary Embodiment 23 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the at least one excipient is not mannitol.
  • Exemplary Embodiment 24 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the at least one excipient is croscarmellose.
  • Exemplary Embodiment 25 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the at least one excipient is microcrystalline cellulose.
  • Exemplary Embodiment 26 The pharmaceutical formulation of Exemplary Embodiment 1, wherein the at least one excipient is magnesium stearate.
  • Exemplary Embodiment 27 A pharmaceutical formulation comprising a compound, a polymer carrier, and a bioavailability enhancer in a weight ratio of about 3:6:1, wherein:
  • the compound is 6-cyano-3-[4-(3-methylamino-lH-pyrazolo[3,4-b]pyridin- 5-yl)-benzylamino]-pyrazine-2-carboxylic acid [l-(3,4-difluoro-phenyl)-ethyl]-amide of Formula (I)
  • the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of from about 90% w/w to about 95% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 28 The pharmaceutical formulation of Exemplary Embodiment 27, wherein the pharmaceutical formulation further comprises mannitol in an amount of about 30% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 29 The pharmaceutical formulation of Exemplary Embodiment 28, wherein the pharmaceutical formulation further comprises croscarmellose in an amount of about 18% w/w of the pharmaceutical formulation.
  • Exemplary Embodiment 30 The pharmaceutical formulation of Exemplary Embodiment 29, wherein the polymer carrier is vinylpyrrolidone-vinyl acetate copolymer and the bioavailability enhancer is d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS).
  • TPGS d-a-tocopheryl polyethylene glycol 1000 succinate
  • Exemplary Embodiment 31 The pharmaceutical formulation of Exemplary Embodiment 29, wherein the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the croscarmellose is absent and sodium starch glycolate is present.
  • Exemplary Embodiment 32 The pharmaceutical formulation of Exemplary Embodiment 29, wherein the formulation has a higher bioavailability compared to the pharmaceutical formulation wherein the compound, the polymer carrier and the bioavailability enhancer are collectively present in an amount of about 50% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation having an intra-granular component comprising:
  • a pharmaceutical formulation having an intra-granular component comprising:
  • magnesium stearate in an amount of about 1% w/w of the pharmaceutical formulation
  • a pharmaceutical formulation having an intra-granular component comprising:
  • magnesium stearate in an amount of about 3% w/w of the pharmaceutical formulation
  • hydroxypropyl methylcellulose (HPMC) capsule shell in an amount of about 10% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation having an intra-granular component comprising:
  • a gelatin capsule shell an amount from about 5% w/w to about 25% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation having an intra-granular component comprising:
  • a hydroxypropyl methylcellulose (HPMC) capsule shell in an amount from about 5% w/w to about 25% w/w of the pharmaceutical formulation.
  • a pharmaceutical formulation having an intra-granular component comprising:
  • microcrystalline cellulose in an amount of about 25% w/w of the pharmaceutical formulation
  • magnesium stearate in an amount of about 3% w/w of the pharmaceutical formulation
  • Exemplary Embodiment 39 The pharmaceutical formulation of any one of Exemplary Embodiments 33-38, wherein the copolymer is vinylpyrrolidone-vinyl acetate copolymer, hydroxy propyl methylcellulose, hydroxy propyl methylcellulose acetate succinate copolymer, or polyvinylpyrrolidone.
  • Exemplary Embodiment 40 The pharmaceutical formulation of any one of Exemplary Embodiments 33-38, wherein the copolymer is poly(l-vinylpyrrolidone-co-vinyl acetate).
  • Exemplary Embodiment 41 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 1.
  • Exemplary Embodiment 42 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 25.
  • Exemplary Embodiment 43 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 31.
  • Exemplary Embodiment 44 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 34.
  • Exemplary Embodiment 45 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 35.
  • Exemplary Embodiment 46 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 36.
  • Exemplary Embodiment 47 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 37.
  • Exemplary Embodiment 48 A method of treating cancer in a patient in need thereof, comprising administering to the patient the pharmaceutical formulation of Exemplary Embodiment 38.
  • PDK1 amino acids 51-359
  • AKT2 amino acids 140-467 fused to PIFtide, amino acids EEQEMFRDFDYIADW
  • Enzyme activity was determined in a coupled PDKl/AKT/FAM-crosstide assay and phosphorylation of FAM-crosstide was determined by standard IMAP protocol (Molecular Devices).
  • compounds were titrated 4-fold in DMSO and diluted 40-fold into assay buffer (10 mM Tris HC1 pH7.2; 10 mM MgC12; 0.01% Triton X-100; 1 mM DTT) containing PDK1, AKT2, and FAM-crosstide (final concentrations: 0.75 nM PDK1, 10 nM unphosphorylated AKT2, and 100 nM crosstide substrate).
  • the kinase reaction was initiated by adding ATP to a final concentration of 40 pM of PDK1 and incubated at 25 °C for 30 min.
  • the kinase reaction was combined with Progressive Binding Solution (1 :600 Progressive Binding Reagent, 50% Buffer A, 50% Buffer B, Molecular Devices) in a 1 :3 ratio. The mixture was incubated for 2 hours at 25 °C and the plate was scanned on an Analyst AD with excitation at 485 nm and emission at 530 nm.
  • the fluorescence polarization value “P” is defined by the equation below.
  • the value “mP” is generated by multiplying the P value for each reaction well by a factor of 1000.
  • the value “AmP” for each well is the mP value for that well minus the mP value for the average negative control.
  • PC-3 cells were harvested by trypsin and counted. Cells were plated in coated 96-well flat bottom plates (plate 15,000 cells/well in lOOul growth media (10% FBS, IX pen-strep) an placee in an incubator overnight.
  • Subject inhibitors were were stocked at at 50mM, then diluted to 30mM (4.8 pl cpd plus 1.6ul DMSO) in 100% DMSO. Three-fold dilutions were performed from 30mM stock. (4 pl into 8ul 100% DMSO). Aliquots of 1.0 pl of inhibitor solution were transferred into SF Medium (using deep well block).
  • Control wells were prepared as follows. For DMSO high controls, 1.0 pl of 100% DMSO was added into 1.0ml SF. For low controls for PC-3 cells, 5 pM of Wortmannin (10 pl of ImM Wortmannin stock was added into 2ml SF Medium. The supernatant media was removed and the plate was blotted. lOOpl of controls/media or compound/media were added to cells and placed in incubator for 2 hours. The supernatant media was removed and the plate was blotted. 55 pl of the MSD complete lysis buffer was added (10 mis Tris Lysis buffer, 200ul protease inhibitor, lOOul phosphatase inhibitor 1, and lOOul phosphatase inhibitor II). The plate was placed on a plate shaker for 60 mins at 4 deg.
  • MSD plates were blocked for 1 hour by adding 150 pl of Blocking Solution (3% BSA) to each well.
  • the MSD plates were washed 4X with TBST, and 50 pl lysates were transferred to MSD plate and place on plate shaker shake at 4 degrees O/N, light shaking (speed 3.5).
  • the plate was washed 4X with TBST.
  • the following detection antibody solution was used: 1ml Blocking Solution (3% BSA stock, 1% BSA final); 2mls TBST! and 91 pl of stock (0.33uM) detection antibody (final concentration lOnM). 25 pl of Ab detection solution was added to each well. The plate was sealed and incubated Cup RT, light shaking (speed 3.5). The plate was washed 4 times with TBST. 150 pl of Read Buffer was added (5mls 4x MSD Read Buffer + 15mls water). Finally the plate was read immediately on the MSD plate reader.
  • PC-3 cultured in F12K media - Invitrogen cat# 21127-030 plus 10% FBS and IX pen-strep
  • Mesoscale Discovery phospho-akt (Thr 308) kit - cat# K151DYD-1 (includes MSD plate, Tris Wash Buffer, Blocking Solution A, Read buffer, Tris Lysis Buffer, protease inhibitor, phosphatase inhibitor I, phosphatase inhibitor II, and detection)
  • Wortmannin - Calbiochem cat# 681675 (ImM stock, aliquoted and stored at -20deg); and 96 well Poly-L-Lysine coated plates - Becton Dickinson cat# 35-4516 (stored at room temp).
  • Hot melt extrusion shows significantly higher dissolution in gastric phase (GB), aids in maintaining intestinal phase (IB) supersaturation. However, it does not sustain well.
  • HPMCAS spray dry intermediate (SDI) has slightly higher dissolution in GM than in FaSSIF with high variability at final time point.
  • formulations comprising 15:85 and 30:70 Compound of Formula (I):HPMCAS-M SDDs, 15:85 Compound of Formula (I):HPMC SDD, 15:85 Compound of Formula (I):PVPVA SDD have better properties than the other formulations.
  • HPMCAS SDDs showed sustainment after transfer to IB.
  • Results show that PVP-K30 formulations required addition of methanol to dissolve polymer. All yields are within expected range. Residual THF levels were high for PVP and PVPVA SDDs indicating the secondary drying process will need to be optimized to get below ICH limits of 720ppm.
  • the compound of Formula (I) API was characterized by XRPD.
  • the XRPD diffraction pattern is provided in Figure 5.
  • API has diffraction pattern consistent with crystalline material. Melt-Quench by DSC
  • T m / T g 1.37 generally indicates a propensity to crystallize, however, the Tg is high which may mitigate that risk.
  • API recrystallizes after the T g which can also be an indication of propensity to crystallize.
  • API consists of long, thin acicular particles.
  • Drug loading 15%, 30% Lower drug loading should help to increase solubility and help with sustainment of solubilized drug.
  • the following polymers were considered as candidates: PVP K30, PVP-VA, HPMCAS M, and HPMC E3LV.
  • Another candidate is Eudragit which has a suitable Cmax and potentially good sustainment, particularly at the higher loading.
  • Another option is Cellulose acetate phthalate (CAP) which has a suitable Cmax and good sustainment. Phthalates tend to hydrolyze off the polymer on storage, particularly at high humidity conditions.
  • CAP Cellulose acetate phthalate

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Abstract

La présente divulgation concerne des formulations pharmaceutiques, pour le traitement du cancer, et des méthodes pour la préparation de telles compositions. L'invention concerne également des méthodes d'administration de telles formulations pharmaceutiques à des patients pour le traitement du cancer.
PCT/US2023/072503 2022-08-19 2023-08-18 Formulations pharmaceutiques, processus de préparation et méthodes d'utilisation WO2024040241A1 (fr)

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