US2019127359A1PendingUtilityA1
Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
Est. expiryJan 12, 2032(~5.5 yrs left)· nominal 20-yr term from priority
Inventors:Craig M. CrewsDennis BuckleyAlessio CiulliWilliam L. JorgensenPeter GareissInge Van MolleJeffrey L. GustafsonHyun Seop TaeJulien MichelDenton W. HoyerAnke Gundula RothJohn David HarlingIan Edward David SmithAfjal Hussain MiahSebastien Andre CamposJoelle Le
A61P 43/00A61P 7/04A61P 7/00A61P 3/10A61P 35/02A61P 37/04A61P 35/00A61P 9/12A61P 9/10A61P 9/00A61P 25/24A61P 25/28A61P 31/18A61P 25/08A61P 25/18A61P 25/16A61P 31/14A61P 29/00A61P 3/04A61P 11/06A61P 17/02A61P 21/02A61P 25/00A61P 1/04A61P 15/00A61K 31/422C07J 43/003C07D 413/14C07D 417/12C07D 471/04C07D 405/06A61K 31/454C12N 9/93A61K 31/437C07D 405/12C07D 207/26C07D 413/12A61K 31/4439A61K 47/545C07D 403/06A61K 31/5377A61K 38/05A61K 47/55C07D 413/06C07D 401/06C07D 417/14A61K 31/427C07D 207/16A61K 47/64C07D 401/10A61K 38/06A61K 45/06G01N 33/5008C07D 417/10C07D 413/10C07D 403/10A61K 31/58
54
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Claims
Abstract
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of chemical structure:
ULM-L-PTM,
wherein:
L is a bond or a chemical linker coupling the ULM to the PTM;
PTM is a moiety that binds to a target protein or polypeptide which is to be ubiquiniated by VHL; and
ULM is a small molecule Von Hippel Lindau E3 ubiquitin ligase (VHL) binding moiety of formula:
wherein
R 1′ is —OH or a group which can be metabolized to —OH;
R 2′ is selected from the group consisting of optionally substituted —NR 1 —X R2′ -alkyl group, optionally substituted —NR 1 —X R2′ -Aryl group; optionally substituted —NR 1 —X R2′ -HET group, optionally substituted —NR 1 —X R2′ -Aryl-HET group, and optionally substituted —NR 1 —X R2′ -HET-Aryl group;
R 1 is H or C 1 -C 3 alkyl;
X R2′ is optionally substituted —(CH 2 ) n —, —(CH 2 ) n —C(X v )═C(X v )— (cis or trans), —(CH 2 ) n —C≡C—, —(CH 2 CH 2 O) n — or C 3 -C 6 cycloalkyl;
R 3′ is optionally substituted C 1 -C 6 alkyl, optionally substituted —(CH 2 ) n —(V) n′ —(CH 2 ) n —(V) n′ —R S3′ group, optionally substituted —(CH 2 ) n —N(R 1′ )(C═O) m′ —(V) n′ —R S3′ group, optionally substituted —X R3′ -alkyl group, optionally substituted —X R3′ -Aryl group, optionally substituted —X R3′ -HET group, optionally substituted —X R3′ -Aryl-HET group, or optionally substituted —X R3′ -HET-Aryl group;
R S3′ is optionally substituted C 1 -C 6 alkyl, optionally substituted Aryl group, or a HET group;
R 1′ is H or C 1 -C 3 alkyl;
V is O, S, or NR 1′ ;
X R3′ is optionally substituted —(CH 2 ) n —, —(CH 2 ) n —CH(X v )═CH(X v )— (cis or trans), —(CH 2 ) n —CH≡CH—, —(CH 2 CH 2 O) n — or C 3 -C 6 cycloalkyl;
X v is H, halo or C 1 -C 3 alkyl which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;
Alkyl is optionally substituted C 1 -C 6 alkyl;
Aryl is optionally substituted phenyl or naphthyl;
HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline or a group of chemical structure:
wherein
S c is CHR SS , NR URE , or O;
R HET is H, CN, NO 2 , halo, optionally substituted C 1 -C 6 alkyl, optionally substituted O(C 1 -C 6 alkyl) or optionally substituted acetylenic group —C≡C—R a , where R a is H or C 1 -C 6 alkyl;
R SS is H, CN, NO 2 , halo, optionally substituted C 1 -C 6 alkyl, optionally substituted O—(C 1 -C 6 alkyl) or optionally substituted —C(O)(C 1 -C 6 alkyl);
R URE is H, C 1 -C 6 alkyl, or a —C(O)(C 1 -C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogens, or optionally substituted heterocycle; and
Y C is N or C—R YC , where R YC is H, OH, CN, NO 2 , halo, optionally substituted C 1 -C 6 alkyl, optionally substituted O(C 1 -C 6 alkyl) or optionally substituted —C≡C≡C—R a group, where R a is defined as above;
R PRO is H, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine;
R PRO1 and R PRO2 are each independently H, optionally substituted C 1 -C 3 alkyl, or together form a keto group;
m′ is 0 or 1;
each n is independently 0, 1, 2, 3, 4, 5, or 6;
each n′ is independently 0 or 1;
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.
2 . The compound of claim 1 , wherein ULM is a group of chemical structure:
wherein
R 1′ is —OH or a group which can be metabolized in a patient or subject to —OH;
R 2′ is a —NR 1 —X R2′ -Aryl or —NR 1 —X R2′ -Aryl-HET, wherein Aryl and HET are independently optionally substituted with at least one selected from the group consisting of alkyl, alkoxy, halogen, acid, ester, cycloalkyl and heterocycloalkyl;
X R2′ is optionally substituted —(CH 2 )n;
R 3′ is optionally substituted alkyl, —(CH)R CR3′ —NH—C(O)—R 3P1 or —(CH)R CR3′ —R 3P2 group;
R CR3′ is optionally substituted C 1 -C 4 alkyl;
R 3P1 is optionally substituted C 1 -C 6 alkyl, optionally substituted oxetane group, —(CH 2 ) n OCH 3 wherein n is 1 or 2, or optionally substituted phenyl group, or a morpholino group linked to the carbonyl at the 2- or 3-position;
R 3P2 is
or optionally substituted aryl;
HET is optionally substituted thiazole, oxazole, isoxazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, and quinolone, wherein the substitution is independently a C1-C3 alkyl group, or a halo group;
R HET is H, halo, CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, or optionally substituted aryl; and
the ULM group is covalently bonded to a linker group to which is attached a PTM group,
or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
3 . The compound of claim 2 , wherein the ULM is selected from the group consisting of:
wherein the ULM group is covalently bonded to a linker group to which is attached a PTM group,
or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.
4 . The compound of claim 1 , wherein the ULM is
wherein
X is Cl, F, C 1 -C 3 alkyl, or an optionally substituted heterocycle;
R 1 and R 2 are each independently H, C 1 -C 3 alkyl, or phenyl; and
the ULM group is substituted with a linker group or a linker group to which is optionally attached a PTM group, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof.
5 . The compound of claim 1 , wherein the ULM group is:
wherein
n is 0 or 1;
R is a linker or a linker attached to a PTM group linked to the ULM group through an amide, ester, ether, carbamate or heterocyclic group; and
X is independently is H, F, Cl, C 1 -C 3 alkyl optionally substituted with one or two hydroxyl groups, heterocyle, —O—C(O)NR 3 R 4 or —C(O)NR 3 R 4 , wherein each of R 3 and R 4 is independently H, C 1 -C 3 alkyl, or phenyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.
6 . The compound of claim 1 , wherein L is at least one member selected from the group consisting of a bond, —(CH 2 ) i —O—, —(CH 2 —CH 2 —O) i —, —(CH 2 ) i —S—, —(CH 2 ) i —NR—, —(CH 2 ) i —X 1 Y 1 —,
and any combinations thereof, wherein
each i is independently 0 to 100;
R is H, C 1 -C 3 alkyl, an alkanol group, or a heterocyclic group;
Y is independently a bond, O, S or N—R;
X 1 Y 1 forms an amide group, a urethane group, ester or thioester group;
D is independently a bond (absent),
j is an integer ranging from 1 to 100;
k is an integer ranging from 1 to 100;
m′ is an integer ranging from 1 to 100;
n is an integer ranging from 1 to 100; and
X 1 is O, S or N—R; and
CON is a bond (absent), a piperazinyl group, optionally substituted alkylene, heterocycle,
X 2 is O, S, NR 4 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
X 3 is O, S, CHR 4 or NR 4 ; and
R 4 is H or a C 1 -C 3 alkyl group, which is optionally substituted with one or two hydroxyl groups.
7 . The compound of claim 6 , wherein i is 1 to 10.
8 . The compound of claim 6 , wherein L is a (poly)ethyleneglycol having from 1 to 100 ethylene glycol units.
9 . The compound of claim 6 , wherein R is morpholino, piperidinyl, or piperazinyl.
10 . The compound of claim 6 , wherein CON is a
group, an amide group, or a piperazinyl group.
11 . The compound of claim 1 , wherein the ULM is selected from the group consisting of:
wherein the ULM is modified to be covalently bonded to the PTM group through a linker group, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate, or polymorph thereof.
12 . The compound of claim 1 , wherein the ULM is a member selected from the group consisting of:
wherein the ULM is modified to be covalently bonded to the PTM group through a linker group, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, polymorph or prodrug thereof.
13 . A compound selected from the group consisting of
wherein each of R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC and R 14PC is are each independently H or a
group; and
wherein L is a linker group and PTM is a protein targeting moiety, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate, or polymorph thereof.
14 . The compound of claim 13 , which is:
wherein R 7PC and R 10PC are each independently a
group or H, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate, or polymorph thereof.
15 . The compound of claim 13 , which is:
wherein R 7PC , R 11PC R 12PC , R 13PC and R 14PC are each independently a
group or H, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate, or polymorph thereof.
16 . The compound of claim 13 , which is:
wherein R 7PC , R 8PC , R 9PC , R 10PC are R each independently a
group or H, or a pharmaceutically acceptable salt, enantiomer, diasteromer, solvate, or polymorph thereof.
17 . The compound of claim 1 , wherein the linker group is a polyethylene group comprising from 1 to 10 ethylene glycol units.
18 . The compound of claim 1 , wherein the PTM group is a moiety which binds to a target protein selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bcl, Bax, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase, PDE IV phosphodiesterase, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G Protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, H1V 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 Ick, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40/CD40L, newokinin receptor, inosine monophosphate dehydrogenase, p38 MAP Kinase, Ras, Raf, MEK, ERK, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinase, PI3-kinase, focal adhesion kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein 5 alpha reductase, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y receptor, adenosine receptor, adenosine kinase, AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyl transferase, TrkA a receptor beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2, EGF receptor tyrosine kinase, IGFR, FKBP ecdysone 20-monooxygenase, GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, Acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, enolpyruvylshikimate-phosphate synthase.
19 . The compound of claim 1 , wherein the PTM group is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, a humanMDM2 inhibitor, a compound which targets human BET Bromodomain-containing proteins, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressive compound, a compound targeting an aryl hydrocarbon receptor, a compound targeting an androgen receptor, a compound targeting an estrogen receptor, a compound targeting a thyroid hormone receptor, a compound targeting a growth factor receptor, a focal adhesion kinase inhibitor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease or a compound targeting acyl protein thioesterase 1 or 2.
20 . The compound of claim 18 , wherein the PTM group is selected from the group consisting of:
derivatized YKB:
wherein a linker moiety L or a
group is attached via the terminal amide group;
derivatized p54:
wherein a linker moiety or a
group is attached via the terminal acetylene group;
derivatized (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide) having the structure:
wherein a linker moiety L or a
group is attached via the amide group or a hydroxyl group; derivatized PU3:
wherein a linker moiety L or a
group is attached via the butyl group;
derivatized Geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] wherein a linker or a
group is attached via the amide group;
derivatized tanespimycin(17-alkylamino-17-desmethoxygeldanamycin (17-AAG)) wherein a linker or a
group is attached via the amide group;
derivatized 17-(2-dimethyl aminoethyl)amino-17-desmethoxygeldanamycin (17-DMAG),
wherein a linker or a
group is attached via the amide group;
derivatized erlotinib:
wherein R is a linker moiety L or a
group attached via the ether group;
derivatized sunitinib:
wherein R is a linker moiety L or a
group which is attached to the pyrrole moiety;
derivatized sorafenib:
wherein R is a linker moiety L or a
group attached to the phenyl moiety;
derivatized dasatinib:
wherein R is a linker moiety L or a
group attached to the pyrimidine;
derivatized lapatinib:
wherein a linker moiety L or a
group is attached via the terminal methyl of the sulfonyl methyl group;
derivatized U09-CX-5279:
wherein a linker moiety L or a
group is attached via the amine (aniline), carboxylic acid or cyclopropyl group;
derivatized Y1X:
wherein a linker moiety L or a
group is attached via the propyl group;
derivatized Y1W:
wherein a linker moiety L or a
group is attached via the propyl group or the tert-butyl group;
derivatized 6TP:
wherein a linker moiety L or a
group is attached via the terminal methyl group bound to amide moiety;
derivatized OTP:
wherein a linker moiety L or a
group is attached via the terminal methyl group bound to the amide moiety;
derivatized 07U:
wherein a linker moiety L or a
group is attached via the secondary amine or terminal/primary amino group;
derivatized YCF:
wherein a linker moiety L or a
group is attached via either of the terminal hydroxyl groups;
derivatized XK9:
wherein a linker moiety L or a
group is attached via the terminal hydroxyl group;
derivatized NXP:
wherein a linker moiety L or a
group is attached via an amine group;
derivatized afatinib, wherein a linker moiety L or a
group is attached via the aliphatic amine group;
derivatized fostamatinib, wherein a linker moiety L or a
group is attached via a methoxy group;
derivatized gefitinib:
wherein a linker moiety L or a
group is attached via a methoxy or ether group;
derivatized lenvatinib, wherein a linker moiety L or a
group is attached via the cyclopropyl group;
derivatized vandetanib, wherein a linker moiety L or a
group is attached via the methoxy or hydroxyl group;
derivatized vemurafenib, wherein a linker moiety L or a
group is attached via the sulfonyl propyl group;
derivatized imatinib:
wherein R is a linker moiety L or a
group attached via the amide group or optionally the L or
group is attached via the aniline amine group;
derivatized pazopanib:
wherein R is a linker moiety L or a
group attached to the phenyl moiety or optionally the L or a
group is attached via the aniline amine group;
derivatized AT-9283:
wherein R is a linker moiety L or a
group attached to the phenyl moiety;
derivatized TAE684:
wherein R is a linker moiety L or a
group which is attached to the phenyl moiety;
derivatized nilotinib:
wherein R is a linker moiety L or a
group attached to the phenyl moiety or optionally L or a
group is attached via an aniline amine group;
derivatized NVP-BSK805:
wherein R is a linker moiety L or a
group attached to a phenyl moiety or optionally L or a
group is attached via the diazole group;
derivatized crizotinib:
wherein R is a linker moiety L or a
group which is attached to the diazole group or optionally L or a
group is attached via a phenyl moiety;
derivatized:
wherein R is a linker moiety L or a
group attached to the phenyl moiety;
derivatized foretinib:
wherein R is a linker moiety L or a
group which is attached to the phenyl moiety or a hydroxyl or ether group on the quinoline moiety;
derivatized PTP1B:
wherein a linker group L or a
group is attached at R;
derivatized inhibitor of SHP-2 domain of tyrosine phosphatase:
wherein a linker group L or a
group is attached at R;
derivatized inhibitor of BRAF (BRAF V600E )/MEK:
wherein a linker L or a
group is attached at R;
derivatized inhibitor of tyrosine kinase ABL:
wherein R is a linker group L or a
group;
derivatized nutlin-3:
wherein a linker moiety L or a
group is attached at the methoxy group or via a hydroxyl linkage;
derivatized nutlin-2:
wherein a linker moiety L or a
group is attached at the methoxy group or via a hydroxyl group;
derivatized nutlin-1:
wherein a linker moiety or a
group is attached via the methoxy group or via a hydroxyl group;
derivatized trans-4-Iodo-4′-Boranyl-Chalcone, wherein a linker moiety L or a
group is attached via a hydroxy group;
a derivatized compound targeting human BET Bromodomain-containing protein Brd2, Brd3, Brd4 selected from the group consisting of:
wherein R is a linker L group or a
group;
derivatized SAHA:
wherein R is a linker group L or a
group;
derivatized BIX-01294:
wherein each R is independently a linker group L or a
group;
derivatized UNC0244:
wherein each R is independently a linker group L or a
group;
derivatized azacitidine, wherein a linker group L or a
group is attached via the hydroxy or amino groups;
derivatized decitabine, wherein a linker group L or a
group is attached via either of the hydroxy groups or at the amino group;
derivatized GA-1;
derivatized estradiol;
derivatized dihydroxytestosterone;
derivatized ovalicin;
derivatized fumagillin;
derivatized AP21998;
a derivatized glucocorticoid selected from the group consisting of hydrocortisone, prednisone, prednisolone, methylprednisoloneand beclometasone dipropionate, wherein a linker group L or a
group is attached;
derivatized methotrexate, wherein a linker group L or a
group is attached to either of the terminal hydroxyls;
derivatized ciclosporin, wherein a linker group L or a
group is attached at any of the butyl groups;
derivatized tacrolimus (FK-506) or rapamycin, wherein a linker group L or a
group is attached at one of the methoxy groups;
derivatized actinomycin, wherein a linker group L or a
group is attached at one of the isopropyl groups;
a derivatized compound targeting the aryl hydrocarbon receptor (AHR) selected from the group consisting of Apigenin, SR1 and LGC006, wherein a linker group L or a
group is attached;
derivatized PLX4032:
wherein R designates a linker group L or a
group;
a derivatized compound targeting FKBP according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized compound targeting androgen receptor (AR) according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized SARM ligand of Androgen Receptor according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized Androgen Receptor Ligand DHT according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized compound targeting Estrogen Receptor (ER) according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized compound targeting Thyroid Hormone Receptor (TR) according to the chemical structure:
wherein R designates a linker group L or a
group and MOMO indicates a methoxymethoxy group;
a derivatized compound targeting HIV Protease according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized Inhibitor of HIV Integrase according to the chemical structure:
wherein R designates a linker group L or a
group;
a derivatized compound targeting HCV Protease according to the chemical structure:
wherein R designates a linker group L or a
group; and
a derivatized compound targeting Acyl-protein Thioesterase-1 and -2 (APT1 and APT2) according to the chemical structure:
wherein R designates a linker group L or a
group.
21 . A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically suitable carrier.
22 . A method of regulating the amount or activity of a target protein in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 2 .
23 . The method of claim 22 , wherein the target protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, aromatases, motor activity proteins, helicases, proteolytic proteins, kinases, oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, enzyme regulators, signal transduction proteins, lipid binding proteins, carbohydrate binding proteins, receptors, cell motility proteins, membrane fusion proteins, cell communication proteins, developmental proteins, cell differentiation proteins, cell adhesion proteins, pro- and anti-apoptotic proteins, transport proteins, nuclear transport proteins, hormone receptors, ion transporter proteins, carrier proteins, permeases, secretory proteins, electron transport tproteins, chaperone regulator proteins, nucleic acid binding proteins, transcription regulatory proteins, and translation regulator proteins.
24 . The method of claim 22 , wherein the target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apotosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e., Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, multi drug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5 alpha reductase inhibitors, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptor, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channels, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.
25 . A method of treating a disease state or condition in a patient, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 2 , wherein the compound regulates the amount or activity of a target protein in the subject, wherein the target protein's dysregulated amount or activity is responsible for the disease state or condition in the subject.
26 . The method of claim 25 , wherein the disease state is cancer.
27 . The method of claim 26 , wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratocarcinomas.
28 . The method of claim 26 , wherein the cancer is T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML
29 . The method of claim 25 , wherein the disease state is prostate cancer, Kennedy's Disease, breast cancer, Lymphoma, diabetes, diabetes melittus type I, diabetes melittus type II, obesity, colorectal cancer, head & neck cancer, immune system disorders, leukemia, stem cell growth, wound healing, atherosclerosis, hepatocellular carcinoma, endometrial cancer, McCune-Albright Syndrome, adenocarcinoma, acute lymphoblastic leukemia (ALL), myeloproliferative diseases, and large B-cell lymphoma.
30 . A method of degrading a target protein in a cell, wherein the method comprises contacting the cell with an effective amount of the compound of claim 1 , wherein the compound promotes degradation of the target protein in the cell.Cited by (0)
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