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Richard W Heidebrecht,
Melissa Chenard,
Joshua Close,
William K Dahlberg,
Judith Fleming,
Jonathan B Grimm,
Julie E Hamill,
Andreas Harsch,
Brian B Haines,
Bethany Hughes, Astrid M Kral,
Richard E Middleton,
Chandrasekhar Mushti,
Nicole Ozerova,
Alexander A Szewczak,
Hongmei Wang,
Kevin Wilson,
David J Witter,
J Paul Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
Bioorganic & medicinal chemistry letters 05/2009; 19(7):2053-8. · 2.65 Impact Factor
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Solomon D Kattar,
Laura M Surdi,
Anna Zabierek,
Joey L Methot,
Richard E Middleton,
Bethany Hughes,
Alexander A Szewczak,
William K Dahlberg, Astrid M Kral,
Nicole Ozerova, [......],
Hongmei Wang,
Paul Secrist,
Andreas Harsch,
Julie E Hamill,
Jonathan C Cruz,
Candia M Kenific,
Melissa Chenard,
Thomas A Miller,
Scott C Berk,
Paul Tempest
[show abstract]
[hide abstract]
ABSTRACT: The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
Bioorganic & medicinal chemistry letters 01/2009; 19(4):1168-72. · 2.65 Impact Factor
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Anita Y H Lee,
Cloud P Paweletz,
Roy M Pollock,
Robert E Settlage,
Jonathan C Cruz,
J Paul Secrist,
Thomas A Miller,
Matthew G Stanton, Astrid M Kral,
Nicole D S Ozerova,
Fanyu Meng,
Nathan A Yates,
Victoria Richon,
Ronald C Hendrickson
[show abstract]
[hide abstract]
ABSTRACT: Inhibitors of class 1 and class 2 histone deacetylase (HDAC) enzymes have shown antitumor activity in human clinical trials. More recently, there has been interest in developing subtype-selective HDAC inhibitors designed to retain anticancer activity while reducing potential side effects. Efforts have been initiated to selectively target HDAC1 given its role in tumor proliferation and survival. The development of HDAC1-specific inhibitors will require the identification of HDAC1-selective pharmacodynamic markers that correlate closely with HDAC1-inhibition in vitro and in vivo. Existing histone markers of HDAC target engagement were developed using pan-HDAC inhibitors and do not necessarily represent robust readouts for isoform-specific inhibitors. Therefore, we have initiated a proteomic approach to identify readouts for HDAC1 inhibition. This approach involves the use of differential mass spectrometry (dMS) to identify post-translational changes in histones by profiling histone-enriched cellular fractions treated with various HDAC inhibitors. In this study, we profiled histones isolated from the HCT116 human colon cancer cell line that have been treated with compounds from multiple chemical classes that are specific for HDAC1; HDAC1 and 3; and HDAC1, 3, and 6 enzymes. In two independent experiments, we identified 24 features that correlated with HDAC1-inhibition. Among the peptides modulated by HDAC1-selective inhibitors were Ac-H2B-K5 from histone H2B, and Ac-H3-K18 from histone H3. Commercially available antibodies to specific histone acetyl-lysine residues were used to confirm that these peptides also provide pharmacodynamic readouts for HDAC1-selective inhibitors in vivo and in vitro. These results show the utility of dMS in guiding the identification of specific readouts to aid in the development of HDAC-selective inhibitors.
Journal of Proteome Research 01/2009; 7(12):5177-86. · 5.11 Impact Factor
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Richard W. Heidebrecht Jr, Melissa Chenard,
Joshua Close,
William K. Dahlberg,
Judith Fleming,
Jonathan B. Grimm,
Julie E. Hamill,
Andreas Harsch,
Brian B. Haines, Bethany Hughes, Astrid M. Kral, Richard E. Middleton
[show abstract]
[hide abstract]
ABSTRACT: We report the preparation and structure–activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
Bioorganic & Medicinal Chemistry Letters - BIOORG MEDICINAL CHEM LETTER. 01/2009; 19(7):2053-2058.
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Solomon D. Kattar,
Laura M. Surdi, Anna Zabierek,
Joey L. Methot, Richard E. Middleton, Bethany Hughes,
Alexander A. Szewczak,
William K. Dahlberg, Astrid M. Kral,
Nicole Ozerova,
Judith C. Fleming,
Hongmei Wang
[show abstract]
[hide abstract]
ABSTRACT: The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.
Bioorganic & Medicinal Chemistry Letters - BIOORG MEDICINAL CHEM LETTER. 01/2009; 19(4):1168-1172.
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Joey L Methot,
Christopher L Hamblett,
Dawn M Mampreian,
Joon Jung,
Andreas Harsch,
Alexander A Szewczak,
William K Dahlberg,
Richard E Middleton,
Bethany Hughes,
Judith C Fleming,
Hongmei Wang, Astrid M Kral,
Nicole Ozerova,
Jonathan C Cruz,
Brian Haines,
Melissa Chenard,
Candia M Kenific,
J Paul Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
Bioorganic & medicinal chemistry letters 11/2008; 18(23):6104-9. · 2.65 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2194-7. · 2.65 Impact Factor
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Zhicai Wu,
Ronald G Robinson,
Sheng Fu,
Stanley F Barnett,
Deborah Defeo-Jones,
Raymond E Jones, Astrid M Kral,
Hans E Huber,
Nancy E Kohl,
George D Hartman,
Mark T Bilodeau
[show abstract]
[hide abstract]
ABSTRACT: This paper describes the rapid assembly of four different classes of potent Akt inhibitors from a common intermediate. Among them, a pyridopyrimidine series displayed the best intrinsic and cell potency against Akt1 and Akt2. This series also showed a promising pharmacokinetic profile and excellent selectivity over other closely related kinases.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):2211-4. · 2.65 Impact Factor
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Kevin J Wilson,
David J Witter,
Jonathan B Grimm,
Phieng Siliphaivanh,
Karin M Otte, Astrid M Kral,
Judith C Fleming,
Andreas Harsch,
Julie E Hamill,
Jonathan C Cruz,
Melissa Chenard,
Alexander A Szewczak,
Richard E Middleton,
Bethany L Hughes,
William K Dahlberg,
J Paul Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
Bioorganic & medicinal chemistry letters 04/2008; 18(6):1859-63. · 2.65 Impact Factor
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Joey L Methot,
Prasun K Chakravarty,
Melissa Chenard,
Joshua Close,
Jonathan C Cruz,
William K Dahlberg,
Judith Fleming,
Christopher L Hamblett,
Julie E Hamill,
Paul Harrington, [......],
Peter T Meinke,
Richard E Middleton,
Nicole Ozerova,
David L Sloman,
Matthew G Stanton,
Alexander A Szewczak,
Sriram Tyagarajan,
David J Witter,
J Paul Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
Bioorganic & medicinal chemistry letters 03/2008; 18(3):973-8. · 2.65 Impact Factor
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Zhicai Wu,
John C Hartnett,
Lou Anne Neilson,
Ronald G Robinson,
Sheng Fu,
Stanley F Barnett,
Deborah Defeo-Jones,
Raymond E Jones, Astrid M Kral,
Hans E Huber,
George D Hartman,
Mark T Bilodeau
[show abstract]
[hide abstract]
ABSTRACT: This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
Bioorganic & medicinal chemistry letters 03/2008; 18(4):1274-9. · 2.65 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Ongoing clinical studies indicate that inhibitors of Class I and Class II histone deacetylase (HDAC) enzymes show great promise for the treatment of cancer. Zolinza (SAHA, Zolinza) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma. As a part of an ongoing effort to identify novel small molecules to target these important enzymes, we have prepared several classes of amino acid-derived HDAC1 inhibitors. The design rationale and in vitro activity against the HDAC1 enzyme and HCT116 cell line are described in this letter.
Bioorganic & medicinal chemistry letters 02/2008; 18(1):34-8. · 2.65 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4-7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.
Bioorganic & medicinal chemistry letters 01/2008; 18(2):726-31. · 2.65 Impact Factor
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Joey L. Methot,
Christopher L. Hamblett,
Dawn M. Mampreian,
Joon Jung,
Andreas Harsch,
Alexander A. Szewczak,
William K. Dahlberg, Richard E. Middleton, Bethany Hughes,
Judith C. Fleming,
Hongmei Wang, Astrid M. Kral
[show abstract]
[hide abstract]
ABSTRACT: A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.
Bioorganic & Medicinal Chemistry Letters - BIOORG MEDICINAL CHEM LETTER. 01/2008; 18(23):6104-6109.
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Christopher L Hamblett,
Joey L Methot,
Dawn M Mampreian,
David L Sloman,
Matthew G Stanton, Astrid M Kral,
Judith C Fleming,
Jonathan C Cruz,
Melissa Chenard,
Nicole Ozerova, [......],
Sujal V Deshmukh,
Naim Nazef,
Andreas Harsch,
Bethany Hughes,
William K Dahlberg,
Alex A Szewczak,
Richard E Middleton,
Ralph T Mosley,
J Paul Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.
Bioorganic & Medicinal Chemistry Letters 11/2007; 17(19):5300-9. · 2.55 Impact Factor
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Phieng Siliphaivanh,
Paul Harrington,
David J Witter,
Karin Otte,
Paul Tempest,
Sam Kattar, Astrid M Kral,
Judith C Fleming,
Sujal V Deshmukh,
Andreas Harsch,
Paul J Secrist,
Thomas A Miller
[show abstract]
[hide abstract]
ABSTRACT: Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are of synthetic and therapeutic interest and ongoing clinical studies indicate that they show great promise for the treatment of cancer. Moreover, Zolinza (vorinostat) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma [Nat. Rev. Drug Disc. 2007, 6, 21]. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of HDAC inhibitors, we sought to identify novel HDAC inhibitor structures through iterative design by utilizing low affinity ligands as synthetic starting points for SAR development. Novel and potent HDAC inhibitors have been identified using this approach and herein we report the optimization of the recognition elements of a novel series of malonyl-derived HDAC inhibitors.
Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4619-24. · 2.55 Impact Factor
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Stanley F Barnett,
Deborah Defeo-Jones,
Sheng Fu,
Paula J Hancock,
Kathleen M Haskell,
Raymond E Jones,
Jason A Kahana, Astrid M Kral,
Karen Leander,
Ling L Lee,
John Malinowski,
Elizabeth M McAvoy,
Debbie D Nahas,
Ronald G Robinson,
Hans E Huber
[show abstract]
[hide abstract]
ABSTRACT: We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.
Biochemical Journal 02/2005; 385(Pt 2):399-408. · 4.90 Impact Factor
