Robert Newton - Academia.edu (original) (raw)
Papers by Robert Newton
The Journal of dermatological treatment, Jan 14, 2016
Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, includi... more Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% f...
Bioorganic Medicinal Chemistry Letters, Jan 15, 2008
Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-a... more Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-a. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability. . TACE inhibitors, cis-a,b-cyclic-b-amino acid scaffolds.
Journal of Medicinal Chemistry, 2002
![Research paper thumbnail of Potent, exceptionally selective, orally bioavailable inhibitors of TNF-α Converting Enzyme (TACE) : Novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents](https://attachments.academia-assets.com/44230133/thumbnails/1.jpg)
](Bioorganic Medicinal Chemistry Letters, 2008
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 ... more Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 substituents in conjunction with unique constrained b-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-a Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-a in human whole blood and orally bioavailable.
![Research paper thumbnail of Α,β -Cyclic-β -benzamido hydroxamic acids : Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-a converting enzyme (TACE)](https://attachments.academia-assets.com/44230159/thumbnails/1.jpg)
](Bioorganic Medicinal Chemistry Letters, 2008
Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-a... more Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-a. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability. . TACE inhibitors, cis-a,b-cyclic-b-amino acid scaffolds.
J Med Chem, 2001
A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the sp... more A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.
Bioorganic Medicinal Chemistry Letters, 2004
In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inh... more In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inhibitors, here a series of novel 4-alkoxy-and 4-acyloxy-phenylethylenethiosemicarbazone analogues were designed, synthesized and their biological activities on mushroom tyrosinase were evaluated. Notably, most of compounds displayed remarkable tyrosinase inhibitory activities with IC 50 value of lower than 1.0 lM. Furthermore, the structure-activity relationships (SARs) were discussed and the inhibition mechanism and the inhibitory kinetics of selected compounds 7k and 8d were also investigated. Taken together, these results suggested that such compounds could serve as the promising candidates for the treatment of tyrosinase-related disorders and further development of such compounds might be of great interest.
Journal of Medicinal Chemistry, Jul 11, 2002
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TAC... more New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
Biochemical and Biophysical Research Communications, May 8, 1997
conversion to PGH 2 by the two cyclooxygenase (COX) Prostaglandin (PG) synthesis during inflammat... more conversion to PGH 2 by the two cyclooxygenase (COX) Prostaglandin (PG) synthesis during inflammation enzymes (1, 2). COX-1 is constitutively expressed (2, occurs mainly via the transcriptionally regulated 3), whilst COX-2 is induced by pro-inflammatory stimcyclooxygenase, COX-2. In pulmonary type II A549 uli and is required for mitogen-dependent PG synthesis cells, Northern analysis identified multiple IL-1b-in-(2-4). These enzymes are the main targets for non-steducible COX-2 mRNA transcripts. Amplification of 3roidal anti-inflammatory drugs (NSAIDs) (1, 2), whose cDNA ends by anchored PCR revealed products coranti-inflammatory effects are thought to derive from responding to the predominant 4.5 and 2.7 kb traninhibition of COX-2, whilst many of the undesirable scripts. Sequence analysis of amplification products side effects are due to COX-1 inhibition (1-3). Use of indicated that these transcripts arose by alternate selective COX-2 inhibitors confirms this and highlights consensus and non-consensus polyadenylation site the role of COX-2 in inflammation (5, 6).
European Journal of Cancer Supplements, 2010
CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC... more CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC tissues by quantitative PCR. Finally, in order to characterize the phenotype of IL-17-positive cells, expression of IL-17, in combination with that of specific surface molecules, was analyzed on freshly excised CRC specimens by flow cytometry. Results: Frequencies of IL-17-producing cells, as well as IL-17 gene expression levels were significantly increased in tumour tissues as compared to autologous normal mucosa. IL-17-producing cells isolated from clinical specimens were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly,Foxp3 molecules. Accordingly, mRNA levels of genes encoding for cytokines favouring IL-17 acquisition by Foxp3+ T cells, including IL-6, IL-1beta, TGF-beta and IL-23, were found more elevated in CRC tissues as comparing to corresponding healthy mucosa. High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, with prolonged survival time in mismatch repair (MMR)-proficient, but not-deficient CRC. Moreover, the simultaneous CRC-infiltration by IL-17+ and Foxp3+ cells was significantly associated with improved survival in both MMR-proficient and -deficient tumours. Conclusions: Our data suggest that IL-17 produced by tumour-infiltrating either CD4+ or Foxp3+ cells may promote a benign clinical outcome in CRC.
Bioorganic & Medicinal Chemistry Letters, 2004
Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-qui... more Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide) with a sulfonyl group led to a new series of α,β-cyclic and β,β-cyclic γ-sulfonyl hydroxamic acids, which were potent TNF-α converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-{[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl}-4-pyrrolidinecarboxamide) exhibited IC50 values of <1nM and 180nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP−1, −2, −9 and
Molecular Cancer Therapeutics, 2013
Journal for ImmunoTherapy of Cancer, 2014
Background: Blockade of immune inhibitory pathways is emerging as an important therapeutic modali... more Background: Blockade of immune inhibitory pathways is emerging as an important therapeutic modality for the treatment of cancer. Single agent treatments have partial anti-tumor activity in preclinical models and in human cancer patients. Inasmuch as the tumor microenvironment shows evidence of multiple immune inhibitory mechanisms present concurrently, it has been reasoned that combination therapies may be required for optimal therapeutic effect.
Neoplasia (New York, N.Y.), 2010
Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal tran... more Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis wa...
European Journal of Cancer Supplements, 2004
The Journal of dermatological treatment, Jan 14, 2016
Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, includi... more Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% f...
Bioorganic Medicinal Chemistry Letters, Jan 15, 2008
Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-a... more Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-a. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability. . TACE inhibitors, cis-a,b-cyclic-b-amino acid scaffolds.
Journal of Medicinal Chemistry, 2002
Bioorganic Medicinal Chemistry Letters, 2008
Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 ... more Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1 0 substituents in conjunction with unique constrained b-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-a Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-a in human whole blood and orally bioavailable.
Bioorganic Medicinal Chemistry Letters, 2008
Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-a... more Two novel oxaspiro[4.4]nonane b-benzamido hydroxamic scaffolds have been synthesized in enantio-and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-a. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability. . TACE inhibitors, cis-a,b-cyclic-b-amino acid scaffolds.
J Med Chem, 2001
A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the sp... more A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.
Bioorganic Medicinal Chemistry Letters, 2004
In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inh... more In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inhibitors, here a series of novel 4-alkoxy-and 4-acyloxy-phenylethylenethiosemicarbazone analogues were designed, synthesized and their biological activities on mushroom tyrosinase were evaluated. Notably, most of compounds displayed remarkable tyrosinase inhibitory activities with IC 50 value of lower than 1.0 lM. Furthermore, the structure-activity relationships (SARs) were discussed and the inhibition mechanism and the inhibitory kinetics of selected compounds 7k and 8d were also investigated. Taken together, these results suggested that such compounds could serve as the promising candidates for the treatment of tyrosinase-related disorders and further development of such compounds might be of great interest.
Journal of Medicinal Chemistry, Jul 11, 2002
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TAC... more New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
Biochemical and Biophysical Research Communications, May 8, 1997
conversion to PGH 2 by the two cyclooxygenase (COX) Prostaglandin (PG) synthesis during inflammat... more conversion to PGH 2 by the two cyclooxygenase (COX) Prostaglandin (PG) synthesis during inflammation enzymes (1, 2). COX-1 is constitutively expressed (2, occurs mainly via the transcriptionally regulated 3), whilst COX-2 is induced by pro-inflammatory stimcyclooxygenase, COX-2. In pulmonary type II A549 uli and is required for mitogen-dependent PG synthesis cells, Northern analysis identified multiple IL-1b-in-(2-4). These enzymes are the main targets for non-steducible COX-2 mRNA transcripts. Amplification of 3roidal anti-inflammatory drugs (NSAIDs) (1, 2), whose cDNA ends by anchored PCR revealed products coranti-inflammatory effects are thought to derive from responding to the predominant 4.5 and 2.7 kb traninhibition of COX-2, whilst many of the undesirable scripts. Sequence analysis of amplification products side effects are due to COX-1 inhibition (1-3). Use of indicated that these transcripts arose by alternate selective COX-2 inhibitors confirms this and highlights consensus and non-consensus polyadenylation site the role of COX-2 in inflammation (5, 6).
European Journal of Cancer Supplements, 2010
CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC... more CRC with full clinico-pathological data. Furthermore, gene expression levels were assessed on CRC tissues by quantitative PCR. Finally, in order to characterize the phenotype of IL-17-positive cells, expression of IL-17, in combination with that of specific surface molecules, was analyzed on freshly excised CRC specimens by flow cytometry. Results: Frequencies of IL-17-producing cells, as well as IL-17 gene expression levels were significantly increased in tumour tissues as compared to autologous normal mucosa. IL-17-producing cells isolated from clinical specimens were exclusively comprised within the lymphocyte population and expressed CD4, but not CD8, and surprisingly,Foxp3 molecules. Accordingly, mRNA levels of genes encoding for cytokines favouring IL-17 acquisition by Foxp3+ T cells, including IL-6, IL-1beta, TGF-beta and IL-23, were found more elevated in CRC tissues as comparing to corresponding healthy mucosa. High infiltration by IL-17 producing cells significantly correlated with low T and N stages, and, most importantly, with prolonged survival time in mismatch repair (MMR)-proficient, but not-deficient CRC. Moreover, the simultaneous CRC-infiltration by IL-17+ and Foxp3+ cells was significantly associated with improved survival in both MMR-proficient and -deficient tumours. Conclusions: Our data suggest that IL-17 produced by tumour-infiltrating either CD4+ or Foxp3+ cells may promote a benign clinical outcome in CRC.
Bioorganic & Medicinal Chemistry Letters, 2004
Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-qui... more Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide) with a sulfonyl group led to a new series of α,β-cyclic and β,β-cyclic γ-sulfonyl hydroxamic acids, which were potent TNF-α converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-{[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl}-4-pyrrolidinecarboxamide) exhibited IC50 values of <1nM and 180nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP−1, −2, −9 and
Molecular Cancer Therapeutics, 2013
Journal for ImmunoTherapy of Cancer, 2014
Background: Blockade of immune inhibitory pathways is emerging as an important therapeutic modali... more Background: Blockade of immune inhibitory pathways is emerging as an important therapeutic modality for the treatment of cancer. Single agent treatments have partial anti-tumor activity in preclinical models and in human cancer patients. Inasmuch as the tumor microenvironment shows evidence of multiple immune inhibitory mechanisms present concurrently, it has been reasoned that combination therapies may be required for optimal therapeutic effect.
Neoplasia (New York, N.Y.), 2010
Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal tran... more Cytokines in the bone marrow of multiple myeloma patients activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways in tumor cells and promote tumor growth, survival, and drug resistance. INCB16562 was developed as a novel, selective, and orally bioavailable small-molecule inhibitor of JAK1 and JAK2 markedly selective over JAK3. The specific cellular activity of the inhibitor was demonstrated by its potent and dose-dependent inhibition of cytokine-dependent JAK/STAT signaling and cell proliferation in the absence of effects on Bcr-Abl-expressing cells. Treatment of myeloma cells with INCB16562 potently inhibited interleukin-6 (IL-6)-induced phosphorylation of STAT3. Moreover, the proliferation and survival of myeloma cells dependent on IL-6 for growth, as well as the IL-6-induced growth of primary bone marrow-derived plasma cells from a multiple myeloma patient, were inhibited by INCB16562. Induction of caspase activation and apoptosis wa...
European Journal of Cancer Supplements, 2004