Natasja Brooijmans

Publications (24)81.36 Total impact

• Article: Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors.

  Christoph M Dehnhardt, Aranapakam M Venkatesan, Zecheng Chen, Efren Delos-Santos, Semiramis Ayral-Kaloustian, Natasja Brooijmans, Ker Yu, Irwin Hollander, Larry Feldberg, Judy Lucas, Robert Mallon
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  ABSTRACT: We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.
  Bioorganic & medicinal chemistry letters 08/2011; 21(16):4773-8. · 2.65 Impact Factor
• Article: Chemical space sampling in virtual screening by different crystal structures.

  Natasja Brooijmans, Christine Humblet
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  ABSTRACT: Retrospective virtual screening experiments were carried out to investigate the effects of combining hit lists from different crystal structures of the same target using consensus scoring. An in-house High Throughput Screening (HTS) dataset from PI3K-γ was used and docked against five diverse PI3K-γ crystal structures. The results show that consensus scoring prioritizes compounds that score moderately against individual crystal structures and is thus complementary to individual crystal structure screening leading to an increase in the diversity of hits. Enrichment factors (EFs) of the consensus score for two or three structures are often as high as or higher than the EF of the individual structures used in the consensus score. Combining four or five structures in the consensus score generally yields lower enrichments. Compounds in the top 500 of the consensus score that are also found in the top 500 of an individual X-ray structure used in the consensus score calculations yield the largest number of hits with the lowest number of false positives.
  Chemical Biology &amp Drug Design 10/2010; 76(6):472-9. · 2.28 Impact Factor
• Article: Biased retrieval of chemical series in receptor-based virtual screening.

  Natasja Brooijmans, Jason B Cross, Christine Humblet
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  ABSTRACT: Using the kinases in the DUD dataset and an in-house HTS dataset from PI3K-γ, receptor-based virtual screening experiments were performed using Glide SP docking. While significant enrichments were observed for eight of the nine targets in the set, more detailed analyses highlighted that much of the early enrichment (10-80%) is the result of retrieval of a single cluster of active compounds. This biased retrieval was not necessarily due to early enrichment of the cluster containing the co-crystallized ligand. Virtual screening validation studies could thus benefit from including cluster-based analyses to assess enrichment of diverse chemotypes.
  Journal of Computer-Aided Molecular Design 10/2010; 24(12):1053-62. · 3.39 Impact Factor
• Article: A protein relational database and protein family knowledge bases to facilitate structure-based design analyses.

  Dominick Mobilio, Gary Walker, Natasja Brooijmans, Ramaswamy Nilakantan, R Aldrin Denny, Jason Dejoannis, Eric Feyfant, Rupesh K Kowticwar, Jyoti Mankala, Satish Palli, Sairam Punyamantula, Maneesh Tatipally, Reji K John, Christine Humblet
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  ABSTRACT: The Protein Data Bank is the most comprehensive source of experimental macromolecular structures. It can, however, be difficult at times to locate relevant structures with the Protein Data Bank search interface. This is particularly true when searching for complexes containing specific interactions between protein and ligand atoms. Moreover, searching within a family of proteins can be tedious. For example, one cannot search for some conserved residue as residue numbers vary across structures. We describe herein three databases, Protein Relational Database, Kinase Knowledge Base, and Matrix Metalloproteinase Knowledge Base, containing protein structures from the Protein Data Bank. In Protein Relational Database, atom-atom distances between protein and ligand have been precalculated allowing for millisecond retrieval based on atom identity and distance constraints. Ring centroids, centroid-centroid and centroid-atom distances and angles have also been included permitting queries for pi-stacking interactions and other structural motifs involving rings. Other geometric features can be searched through the inclusion of residue pair and triplet distances. In Kinase Knowledge Base and Matrix Metalloproteinase Knowledge Base, the catalytic domains have been aligned into common residue numbering schemes. Thus, by searching across Protein Relational Database and Kinase Knowledge Base, one can easily retrieve structures wherein, for example, a ligand of interest is making contact with the gatekeeper residue.
  Chemical Biology &amp Drug Design 08/2010; 76(2):142-53. · 2.28 Impact Factor
• Article: 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.

  Nan Zhang, Semiramis Ayral-Kaloustian, James T Anderson, Thai Nguyen, Sasmita Das, Aranapakam M Venkatesan, Natasja Brooijmans, Judy Lucas, Ker Yu, Irwin Hollander, Robert Mallon
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  ABSTRACT: A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.
  Bioorganic & medicinal chemistry letters 06/2010; 20(12):3526-9. · 2.65 Impact Factor
• Article: Chemical space sampling by different scoring functions and crystal structures.

  Natasja Brooijmans, Christine Humblet
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  ABSTRACT: Virtual screening has become a popular tool to identify novel leads in the early phases of drug discovery. A variety of docking and scoring methods used in virtual screening have been the subject of active research in an effort to gauge limitations and articulate best practices. However, how to best utilize different scoring functions and various crystal structures, when available, is not yet well understood. In this work we use multiple crystal structures of PI3 K-gamma in both prospective and retrospective virtual screening experiments. Both Glide SP scoring and Prime MM-GBSA rescoring are utilized in the prospective and retrospective virtual screens, and consensus scoring is investigated in the retrospective virtual screening experiments. The results show that each of the different crystal structures that was used, samples a different chemical space, i.e. different chemotypes are prioritized by each structure. In addition, the different (re)scoring functions prioritize different chemotypes as well. Somewhat surprisingly, the Prime MM-GBSA scoring function generally gives lower enrichments than Glide SP. Finally we investigate the impact of different ligand preparation protocols on virtual screening enrichment factors. In summary, different crystal structures and different scoring functions are complementary to each other and allow for a wider variety of chemotypes to be considered for experimental follow-up.
  Journal of Computer-Aided Molecular Design 05/2010; 24(5):433-47. · 3.39 Impact Factor
• Article: Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors.

  Zecheng Chen, Aranapakam M Venkatesan, Christoph M Dehnhardt, Semiramis Ayral-Kaloustian, Natasja Brooijmans, Robert Mallon, Larry Feldberg, Irwin Hollander, Judy Lucas, Ker Yu, Fangming Kong, Tarek S Mansour
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  ABSTRACT: Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kalpha and mTOR, leading to the discovery of PI3Kalpha selective inhibitors (e.g., 9) and dual PI3Kalpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kalpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
  Journal of Medicinal Chemistry 03/2010; 53(8):3169-82. · 4.80 Impact Factor
• Article: An enriched structural kinase database to enable kinome-wide structure-based analyses and drug discovery.

  Natasja Brooijmans, Yu-Wei Chang, Dominick Mobilio, Rajiah A Denny, Christine Humblet
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  ABSTRACT: The development of a kinase structural database, the kinase knowledge base (KKB), is described. It covers all human kinase domain structures that have been deposited in the Protein Data Bank. All structures are renumbered using a common scheme, which enables efficient cross-comparisons and multiple queries of interest to the kinase field. The common numbering scheme is also used to automatically annotate conserved residues and motifs, and conformationally classify the structures based on the DFG-loop and Helix C. Analyses of residue conservation in the ATP binding site using the full human-kinome-sequence alignment lead to the identification of a conserved hydrogen bond between the hinge region backbone and a glycine in the specificity surface. Furthermore, 90% of kinases are found to have at least one stabilizing interaction for the hinge region, which has not been described before.
  Protein Science 02/2010; 19(4):763-74. · 2.80 Impact Factor
• Article: Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.

  Aranapakam M Venkatesan, Christoph M Dehnhardt, Efren Delos Santos, Zecheng Chen, Osvaldo Dos Santos, Semiramis Ayral-Kaloustian, Gulnaz Khafizova, Natasja Brooijmans, Robert Mallon, Irwin Hollander, Larry Feldberg, Judy Lucas, Ker Yu, James Gibbons, Robert T Abraham, Inder Chaudhary, Tarek S Mansour
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  ABSTRACT: The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
  Journal of Medicinal Chemistry 02/2010; 53(6):2636-45. · 4.80 Impact Factor
• Article: 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).

  Hwei-Ru Tsou, Gloria MacEwan, Gary Birnberg, Nan Zhang, Natasja Brooijmans, Lourdes Toral-Barza, Irwin Hollander, Semiramis Ayral-Kaloustian, Ker Yu
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  ABSTRACT: A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2259-63. · 2.65 Impact Factor
• Article: Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).

  Hwei-Ru Tsou, Gloria MacEwan, Gary Birnberg, George Grosu, Matthew G Bursavich, Joel Bard, Natasja Brooijmans, Lourdes Toral-Barza, Irwin Hollander, Tarek S Mansour, Semiramis Ayral-Kaloustian, Ker Yu
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  ABSTRACT: We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2321-5. · 2.65 Impact Factor
• Article: Novel benzofuran-3-one indole inhibitors of PI3 kinase-alpha and the mammalian target of rapamycin: hit to lead studies.

  Matthew G Bursavich, Natasja Brooijmans, Lawrence Feldberg, Irwin Hollander, Stephen Kim, Sabrina Lombardi, Kaapjoo Park, Robert Mallon, Adam M Gilbert
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  ABSTRACT: A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110alpha (PI3K-alpha), good pharmaceutical properties, selectivity versus p110gamma (PI3K-gamma), and tunable selectivity versus the mammalian target of rapamycin (mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-alpha and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells.
  Bioorganic & medicinal chemistry letters 02/2010; 20(8):2586-90. · 2.65 Impact Factor
• Article: Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition.

  Christoph M Dehnhardt, Aranapakam M Venkatesan, Zecheng Chen, Semiramis Ayral-Kaloustian, Osvaldo Dos Santos, Efren Delos Santos, Kevin Curran, Max T Follettie, Veronica Diesl, Judy Lucas, Yi Geng, Susan Quinn Dejoy, Rosanne Petersen, Inder Chaudhary, Natasja Brooijmans, Tarek S Mansour, Kim Arndt, Lei Chen
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  ABSTRACT: We are introducing a novel series of 2,4-diaminoquinazolines as beta-catenin/Tcf4 inhibitors which were identified by ligand-based design. Here we elucidate the SAR of this series and explain how we were able to improve key molecular properties such as solubility and cLogP leading to compound 9. Analogue 9 exhibited better biological activity and improved physical and pharmacological properties relative to the HTS hit 49. Furthermore, 9 demonstrated good cell growth inhibition against several human colorectal cancer lines such as LoVo and HT29. In addition, treatment with compound 9 led to gene expression changes that overlapped significantly with the transcriptional profile resulting from the pathway inhibition by siRNA knockdown of beta-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.
  Journal of Medicinal Chemistry 12/2009; 53(2):897-910. · 4.80 Impact Factor
• Article: Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR).

  Joshua Kaplan, Jeroen C Verheijen, Natasja Brooijmans, Lourdes Toral-Barza, Irwin Hollander, Ker Yu, Arie Zask
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  ABSTRACT: The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.
  Bioorganic & medicinal chemistry letters 12/2009; 20(2):640-3. · 2.65 Impact Factor
• Article: Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.

  Christoph M Dehnhardt, Aranapakam M Venkatesan, Efren Delos Santos, Zecheng Chen, Osvaldo Santos, Semiramis Ayral-Kaloustian, Natasja Brooijmans, Robert Mallon, Irwin Hollander, Larry Feldberg, Judy Lucas, Inder Chaudhary, Ker Yu, Jay Gibbons, Robert Abraham, Tarek S Mansour
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  ABSTRACT: Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.
  Journal of Medicinal Chemistry 12/2009; 53(2):798-810. · 4.80 Impact Factor
• Article: Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies.

  Adam M Gilbert, Pawel Nowak, Natasja Brooijmans, Matthew G Bursavich, Christoph Dehnhardt, Efren Delos Santos, Larry R Feldberg, Irwin Hollander, Stephen Kim, Sabrina Lombardi, Kaapjoo Park, Aranapakam M Venkatesan, Robert Mallon
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  ABSTRACT: Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
  Bioorganic & medicinal chemistry letters 12/2009; 20(2):636-9. · 2.65 Impact Factor
• Article: 5-Vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta: optimization of enzymatic and functional activity.

  L Nathan Tumey, Niala Bhagirath, Agnes Brennan, Natasja Brooijmans, Julie Lee, Xiaoke Yang, Diane H Boschelli
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  ABSTRACT: PKCtheta is a serine/threonine kinase involved in the regulation of IL2 production in T cells. It has recently become an attractive therapeutic target for a variety of immunological disorders. We describe the optimization of the enzymatic and cellular potency of a series of 5-vinyl-3-pyridinecarbonitrile inhibitors of PKCtheta. A binding model was developed that explains much of the SAR observed for this series, including the enzymatic potency observed for 19. An analysis of functional potency against various physiochemical parameters suggests that cellular potency is correlated with LogD(7.4), but not with cLogP, PAMPA permeability, or TPSA.
  Bioorganic & medicinal chemistry 12/2009; 17(23):7933-48. · 2.82 Impact Factor
• Article: Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.

  Arie Zask, Joshua Kaplan, Jeroen C Verheijen, David J Richard, Kevin Curran, Natasja Brooijmans, Eric M Bennett, Lourdes Toral-Barza, Irwin Hollander, Semiramis Ayral-Kaloustian, Ker Yu
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  ABSTRACT: Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.
  Journal of Medicinal Chemistry 11/2009; 52(24):7942-5. · 4.80 Impact Factor
• Article: Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors.

  Aranapakam M Venkatesan, Christoph M Dehnhardt, Zecheng Chen, Efren Delos Santos, Osvaldo Dos Santos, Matthew Bursavich, Adam M Gilbert, John W Ellingboe, Semiramis Ayral-Kaloustian, Gulnaz Khafizova, Natasja Brooijmans, Robert Mallon, Irwin Hollander, Larry Feldberg, Judy Lucas, Ker Yu, Jay Gibbons, Robert Abraham, Tarek S Mansour
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  ABSTRACT: This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
  Bioorganic & medicinal chemistry letters 11/2009; 20(2):653-6. · 2.65 Impact Factor
• Article: Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituent.

  Jeroen C Verheijen, David J Richard, Kevin Curran, Joshua Kaplan, Mark Lefever, Pawel Nowak, David J Malwitz, Natasja Brooijmans, Lourdes Toral-Barza, Wei-Guo Zhang, Judy Lucas, Irwin Hollander, Semiramis Ayral-Kaloustian, Tarek S Mansour, Ker Yu, Arie Zask
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  ABSTRACT: Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase alpha (PI3K-alpha), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC(50) against mTOR and greater than 1000-fold selectivity over PI3K-alpha. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM).
  Journal of Medicinal Chemistry 11/2009; 52(24):8010-24. · 4.80 Impact Factor