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1.
J Pharmacol Exp Ther ; 374(1): 211-222, 2020 07.
Article in English | MEDLINE | ID: mdl-32345620

ABSTRACT

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.


Subject(s)
Liver/drug effects , Lymphoma/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/adverse effects , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Pyrimidines/adverse effects , Pyrimidines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/pharmacology , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Immunologic Factors/adverse effects , Immunologic Factors/pharmacology , Mice , Xenograft Model Antitumor Assays
2.
ACS Med Chem Lett ; 10(11): 1554-1560, 2019 Nov 14.
Article in English | MEDLINE | ID: mdl-31749910

ABSTRACT

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

3.
ACS Med Chem Lett ; 8(5): 486-491, 2017 May 11.
Article in English | MEDLINE | ID: mdl-28523098

ABSTRACT

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

4.
Blood ; 115(17): 3520-30, 2010 Apr 29.
Article in English | MEDLINE | ID: mdl-20197554

ABSTRACT

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.


Subject(s)
Dendritic Cells/immunology , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Animals , Apoptosis/drug effects , Apoptosis/immunology , B7-2 Antigen/immunology , B7-2 Antigen/metabolism , Coculture Techniques , Dendritic Cells/enzymology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasms/drug therapy , Neoplasms/enzymology , T-Lymphocytes/enzymology , Tryptophan Oxygenase/immunology , Tryptophan Oxygenase/metabolism
5.
Mol Cancer Ther ; 9(2): 489-98, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20124451

ABSTRACT

Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients.


Subject(s)
Amidines/pharmacology , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Neoplasms/metabolism , Tryptophan/metabolism , Animals , Cell Line, Tumor , Dogs , Female , Humans , Immune System , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Kynurenine/pharmacology , Lymph Nodes/pathology , Lymphocytes/immunology , Mice , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/pathology
6.
J Med Chem ; 52(23): 7364-7, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19507862

ABSTRACT

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.


Subject(s)
Binding, Competitive , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Melanoma/enzymology , Amidines/chemistry , Amidines/metabolism , Amidines/pharmacology , Amidines/therapeutic use , Animals , Disease Models, Animal , Disease Progression , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Inhibitory Concentration 50 , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mice , Models, Molecular , Molecular Conformation
7.
J Med Chem ; 52(14): 4161-72, 2009 Jul 23.
Article in English | MEDLINE | ID: mdl-19552436

ABSTRACT

A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.


Subject(s)
Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Humans , Inhibitory Concentration 50 , Male , Metabolic Clearance Rate , Pyrazines/chemistry , Pyrazines/metabolism , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism
8.
J Med Chem ; 52(14): 4173-91, 2009 Jul 23.
Article in English | MEDLINE | ID: mdl-19552437

ABSTRACT

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.


Subject(s)
Pyrazines/chemistry , Pyrazines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Cell Line, Tumor , Humans , Macaca fascicularis , Male , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 18(1): 66-71, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18037290

ABSTRACT

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazolines/chemical synthesis , Imidazolines/chemistry , Imidazolines/pharmacology , Models, Molecular , Structure-Activity Relationship , Thiazoles/chemical synthesis
10.
J Biol Chem ; 281(49): 38013-21, 2006 Dec 08.
Article in English | MEDLINE | ID: mdl-17028182

ABSTRACT

Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.


Subject(s)
Enzyme Inhibitors/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Thiazoles/chemistry , Catalytic Domain , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Hydrogen Bonding , In Vitro Techniques , Models, Molecular , Protein Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Static Electricity , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology
11.
J Biol Chem ; 281(43): 32784-95, 2006 Oct 27.
Article in English | MEDLINE | ID: mdl-16916797

ABSTRACT

Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.


Subject(s)
Molecular Mimicry , Organophosphonates/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Thiazoles/pharmacology , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Escherichia coli/genetics , Humans , Hydrogen Bonding , Hydrolysis , Inhibitory Concentration 50 , Kinetics , Models, Molecular , Molecular Structure , Protein Conformation/drug effects , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/analysis , Protein Tyrosine Phosphatases/isolation & purification , Structure-Activity Relationship , Substrate Specificity , Water/chemistry
12.
J Med Chem ; 49(13): 3774-89, 2006 Jun 29.
Article in English | MEDLINE | ID: mdl-16789735

ABSTRACT

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.


Subject(s)
Benzimidazoles/chemical synthesis , Oligopeptides/chemistry , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cell Line , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Mimicry , Molecular Structure , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology
13.
Bioorg Med Chem ; 14(17): 5833-49, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16769216

ABSTRACT

The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Peptides/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Escherichia coli , Humans , Models, Molecular , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Structure-Activity Relationship
14.
J Med Chem ; 48(21): 6544-8, 2005 Oct 20.
Article in English | MEDLINE | ID: mdl-16220970

ABSTRACT

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.


Subject(s)
Dipeptides/chemical synthesis , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Thiazoles/chemical synthesis , Crystallography, X-Ray , Dipeptides/chemistry , Drug Design , Models, Molecular , Molecular Mimicry , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Quantitative Structure-Activity Relationship , Stereoisomerism , Thiazoles/chemistry
15.
Bioorg Med Chem Lett ; 14(2): 343-6, 2004 Jan 19.
Article in English | MEDLINE | ID: mdl-14698155

ABSTRACT

New indeno[1,2-c]pyrazol-4-one cyclin dependent kinase inhibitors have been disclosed. The most promising compounds are nanomolar enzyme inhibitors with excellent activity against tumor cells. The most advanced compound retains cell culture activity even in the presence of human serum proteins. The most advanced compound did not kill the normal fibroblast line AG1523.


Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Pyrazoles/chemical synthesis , Cell Line, Tumor , Cyclin-Dependent Kinases/metabolism , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/pharmacology , Fibroblasts/drug effects , Fibroblasts/enzymology , Heterocyclic Compounds/pharmacology , Humans , Pyrazoles/pharmacology
16.
J Med Chem ; 45(24): 5233-48, 2002 Nov 21.
Article in English | MEDLINE | ID: mdl-12431051

ABSTRACT

The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.


Subject(s)
CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Proto-Oncogene Proteins , Pyrazoles/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Cell Division/drug effects , Crystallography, X-Ray , Cyclin-Dependent Kinase 2 , Cyclin-Dependent Kinase 4 , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Kinetics , Models, Molecular , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Pyrazoles/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured
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