Haishan Wang - Academia.edu (original) (raw)
Papers by Haishan Wang
Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetyla... more Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase (HDAC) inhibitor, and prediction of human pharmacokinetics
Bioorganic & Medicinal Chemistry Letters, 2012
Archives of toxicology, Jan 2, 2016
Understanding and predicting whether new drug candidates will be safe in the clinic is a critical... more Understanding and predicting whether new drug candidates will be safe in the clinic is a critical hurdle in pharmaceutical development, that relies in part on absorption, distribution, metabolism, excretion and toxicology studies in vivo. Zebrafish is a relatively new model system for drug metabolism and toxicity studies, offering whole organism screening coupled with small size and potential for high-throughput screening. Through toxicity and absorption analyses of a number of drugs, we find that zebrafish is generally predictive of drug toxicity, although assay outcomes are influenced by drug lipophilicity which alters drug uptake. In addition, liver microsome assays reveal specific differences in metabolism of compounds between human and zebrafish livers, likely resulting from the divergence of the cytochrome P450 superfamily between species. To reflect human metabolism more accurately, we generated a transgenic "humanized" zebrafish line that expresses the major human ...
J Nat Prod, 2001
The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished... more The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished on Sasrin resin. This work confirmed the structure of verrucine A and unambiguously showed verrucine B to be a derivative of D-phenylalanine and L-glutamine. The study also proved that anacine and its epimer are quinazoline alkaloids, not benzodiazepines as originally proposed. 1-Hydroxyverrucine B, derived from air oxidization of verrucine B, was also isolated and characterized.
Ash Annual Meeting Abstracts, Nov 16, 2007
The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylas... more The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to biaryl containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase activities. Formula (I), where Z is a single bond or C1-C4 hydrocarbon, A is an aromatic ring, B is an aromatic ring
Journal of Chemical Information and Modeling, 2014
Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical e... more Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, α, β, γ, and δ, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Kα and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584.
Synthetic Communications, 2003
Molecular Cancer Therapeutics, 2010
Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinic... more Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients.
Journal of Natural Products, 2001
The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished... more The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished on Sasrin resin. This work confirmed the structure of verrucine A and unambiguously showed verrucine B to be a derivative of D-phenylalanine and L-glutamine. The study also proved that anacine and its epimer are quinazoline alkaloids, not benzodiazepines as originally proposed. 1-Hydroxyverrucine B, derived from air oxidization of verrucine B, was also isolated and characterized.
Journal of Medicinal Chemistry, 2012
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycl... more Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Journal of Medicinal Chemistry, 2012
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectiv... more Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
Bioorganic & Medicinal Chemistry Letters, 2012
A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a... more A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serinethreonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.
Archiv der Pharmazie, 2007
A series of 3-aryl-2-(2-thienyl)acrylonitriles 7 and 3-aryl-2-(3-thienyl)acrylonitriles 8 were sy... more A series of 3-aryl-2-(2-thienyl)acrylonitriles 7 and 3-aryl-2-(3-thienyl)acrylonitriles 8 were synthesized by the reaction of aromatic aldehydes 6 with 2-and 3-thienylacetonitriles 4 and 5, and evaluated for antifungal and cytotoxic activities against a panel of opportunistic and pathogenic fungi and three different cancer cell lines, respectively.
The Journal of organic chemistry, Jan 28, 2000
The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazi... more The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazine also feature an oxidative rearrangement of the indole to form a spirooxindole. Synthetically, formation of the oxindole ring was stereoselectively accomplished by reaction of the appropriate indole precursor with N-bromosuccinimide. For optimum results, the oxidation should be carried out prior to diketopiperazine cyclization. In this manner, we have synthesized the tetrahydro- and dihydro- analogues of spirotryprostatin B in four steps from L-tryptophan methyl ester. The dihydro derivative was then converted to spirotryprostatin B by unsaturation of the pyrrolidine ring to a pyrroline, thus unambiguously confirming the structure of the natural product.
Tetrahedron Letters, 1998
The structure of luotonin A was unambiguously confirmed by total synthesis. Deprotonation of 3-ox... more The structure of luotonin A was unambiguously confirmed by total synthesis. Deprotonation of 3-oxo-1H-pyrrolo[3,4-b]quinoline gave an anion which was coupled with 2-sulfinylaminobenzoyl chloride (prepared by reaction of anthranilic acid with thiolyl chloride) to afford the natural product in 85 % yield.
Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetyla... more Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase (HDAC) inhibitor, and prediction of human pharmacokinetics
Bioorganic & Medicinal Chemistry Letters, 2012
Archives of toxicology, Jan 2, 2016
Understanding and predicting whether new drug candidates will be safe in the clinic is a critical... more Understanding and predicting whether new drug candidates will be safe in the clinic is a critical hurdle in pharmaceutical development, that relies in part on absorption, distribution, metabolism, excretion and toxicology studies in vivo. Zebrafish is a relatively new model system for drug metabolism and toxicity studies, offering whole organism screening coupled with small size and potential for high-throughput screening. Through toxicity and absorption analyses of a number of drugs, we find that zebrafish is generally predictive of drug toxicity, although assay outcomes are influenced by drug lipophilicity which alters drug uptake. In addition, liver microsome assays reveal specific differences in metabolism of compounds between human and zebrafish livers, likely resulting from the divergence of the cytochrome P450 superfamily between species. To reflect human metabolism more accurately, we generated a transgenic "humanized" zebrafish line that expresses the major human ...
J Nat Prod, 2001
The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished... more The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished on Sasrin resin. This work confirmed the structure of verrucine A and unambiguously showed verrucine B to be a derivative of D-phenylalanine and L-glutamine. The study also proved that anacine and its epimer are quinazoline alkaloids, not benzodiazepines as originally proposed. 1-Hydroxyverrucine B, derived from air oxidization of verrucine B, was also isolated and characterized.
Ash Annual Meeting Abstracts, Nov 16, 2007
The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylas... more The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to biaryl containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase activities. Formula (I), where Z is a single bond or C1-C4 hydrocarbon, A is an aromatic ring, B is an aromatic ring
Journal of Chemical Information and Modeling, 2014
Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical e... more Phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR) act as critical effectors in a commonly deregulated cell signaling pathway in human cancers. The abnormal activation of the PI3K/mTOR pathway has been shown to play a role in initiation, progression, and metastasis of human tumors. Being one of the most frequently activated pathways in cancer, much effort has been directed toward inhibition of the PI3K/mTOR pathway as a novel oncology therapy. Previous work by a number of groups has revealed several selective PI3K and dual mTOR/PI3K inhibitors. However, there are few reports of therapeutic agents with a pan-PI3K/mTOR inhibitory profile within a narrow concentration range. We therefore initiated a drug discovery project with the aim of discovering dual mTOR/PI3K inhibitors which would equipotently inhibit the 4 isoforms of PI3K, α, β, γ, and δ, and mTOR a compelling profile for powerful blockage of the PI3K/mTOR pathway. A pharmacophore model was generated and used for designing a series of novel compounds, based on a purine scaffold, which potently inhibited mTOR and PI3Ks. These compounds contained a phenol headgroup essential for binding to the target proteins. Early efforts concentrated on finding replacements for the phenol as it was rapidly conjugated resulting in a short half-life in vivo. Compounds with a variety of headgroups were docked into the PI3Kα and mTOR ATP-binding sites, and aminopyrimidine and aminopyrazine were found to make excellent phenol replacements. Further structure guided optimization of side chains in the 8and 9-positions of the purine resulted in potent inhibitors with good PKDM properties. As the PI3 kinases play a role in insulin signaling, it is believed that targeting mTOR selectively may give the benefit of blocking the AKT-pathway while avoiding the potential side effects associated with PI3K inhibition. As a result we designed a further series of selective mTOR kinase inhibitors. The project was successfully concluded by progressing both a dual mTOR/PI3K inhibitor, SB2343, and a selective mTOR inhibitor, SB2602, into preclinical development. SB2343 has since entered phase 1 clinical development as VS-5584.
Synthetic Communications, 2003
Molecular Cancer Therapeutics, 2010
Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinic... more Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients.
Journal of Natural Products, 2001
The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished... more The first total syntheses of verrucines A and B and anacine (revised structure) were accomplished on Sasrin resin. This work confirmed the structure of verrucine A and unambiguously showed verrucine B to be a derivative of D-phenylalanine and L-glutamine. The study also proved that anacine and its epimer are quinazoline alkaloids, not benzodiazepines as originally proposed. 1-Hydroxyverrucine B, derived from air oxidization of verrucine B, was also isolated and characterized.
Journal of Medicinal Chemistry, 2012
Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycl... more Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26 h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
Journal of Medicinal Chemistry, 2012
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectiv... more Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.
Bioorganic & Medicinal Chemistry Letters, 2012
A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a... more A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serinethreonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.
Archiv der Pharmazie, 2007
A series of 3-aryl-2-(2-thienyl)acrylonitriles 7 and 3-aryl-2-(3-thienyl)acrylonitriles 8 were sy... more A series of 3-aryl-2-(2-thienyl)acrylonitriles 7 and 3-aryl-2-(3-thienyl)acrylonitriles 8 were synthesized by the reaction of aromatic aldehydes 6 with 2-and 3-thienylacetonitriles 4 and 5, and evaluated for antifungal and cytotoxic activities against a panel of opportunistic and pathogenic fungi and three different cancer cell lines, respectively.
The Journal of organic chemistry, Jan 28, 2000
The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazi... more The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazine also feature an oxidative rearrangement of the indole to form a spirooxindole. Synthetically, formation of the oxindole ring was stereoselectively accomplished by reaction of the appropriate indole precursor with N-bromosuccinimide. For optimum results, the oxidation should be carried out prior to diketopiperazine cyclization. In this manner, we have synthesized the tetrahydro- and dihydro- analogues of spirotryprostatin B in four steps from L-tryptophan methyl ester. The dihydro derivative was then converted to spirotryprostatin B by unsaturation of the pyrrolidine ring to a pyrroline, thus unambiguously confirming the structure of the natural product.
Tetrahedron Letters, 1998
The structure of luotonin A was unambiguously confirmed by total synthesis. Deprotonation of 3-ox... more The structure of luotonin A was unambiguously confirmed by total synthesis. Deprotonation of 3-oxo-1H-pyrrolo[3,4-b]quinoline gave an anion which was coupled with 2-sulfinylaminobenzoyl chloride (prepared by reaction of anthranilic acid with thiolyl chloride) to afford the natural product in 85 % yield.