- N-Substituted pyrrolopyrimidines and purines as p90 ribosomal S6 protein kinase-2 (RSK2) inhibitors
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The RSK2 kinase is the downstream effector of the Ras/Raf/MEK/ERK pathway, that is often aberrantly activated in acute myeloid leukemia (AML). Recently, we reported a structure-activity study for BI-D1870, the pan-RSK inhibitor, and identified pteridinones that inhibited cellular RSK2 activity that did not result in concomitant cytotoxicity. In the current study, we developed a series of pyrrolopyrimidines and purines to replace the pteridinone ring of BI-D1870, with a range of N-substituents that extend to the substrate binding site to probe complementary interactions, while retaining the 2,6-difluorophenol-4-amino group to maintain interactions with the hinge domain and the DFG motif. Several compounds inhibited cellular RSK2 activity, and we identified compounds that uncoupled cellular RSK2 inhibition from potent cytotoxicity in the MOLM-13 AML cell line. These N-substituted probes have revealed an opportunity to further examine substituents that extend from the ATP- to the substrate-binding site may confer improved RSK potency and selectivity.
- Casalvieri, Kimberly A.,Matheson, Christopher J.,Warfield, Becka M.,Backos, Donald S.,Reigan, Philip
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- Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
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The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
- Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
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supporting information
p. 3956 - 3975
(2021/04/12)
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- Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
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A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
- Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
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p. 15651 - 15670
(2021/11/16)
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- Substituted pteridinones as p90 ribosomal S6 protein kinase (RSK) inhibitors: A structure-activity study
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The activity of p90 ribosomal S6 kinase 2 (RSK2) has emerged as an attractive target for cancer therapy due to its role in the regulation of diverse cellular processes, such as cell transformation and proliferation. Several pan-RSK inhibitors have been identified with BI-D1870 and the pseudo-analogs LJH685 and LJI308 being the most selective, potent, and frequently used small molecule inhibitors. We designed and synthesized a series of pteridinones and pyrimidines to evaluate the structural features of BI-D1870 that are required for RSK2 inhibition. We have identified inhibitors of RSK2 activity, evaluated their target engagement in cells, and measured their effect on cell viability and cytotoxicity in the MOLM-13 acute myeloid leukemia (AML) cell line. The results of our studies support that RSK2 inhibition can be achieved in MOLM-13 cells without potent cytotoxicity. The structure-activity data from this study will be used as a platform to develop novel RSK2 inhibitors.
- Backos, Donald S.,Casalvieri, Kimberly A.,Matheson, Christopher J.,Reigan, Philip
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- Benzothiazolyl ureas are low micromolar and uncompetitive inhibitors of 17Β-HSD10 with implications to Alzheimer’s disease treatment
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Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1–2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
- Aitken, Laura,Benek, Ondrej,Chribek, Matej,Dolezal, Rafael,Gunn-Moore, Frank,Hrabinova, Martina,Hroch, Lukas,Jun, Daniel,Kralova, Vendula,Kuca, Kamil,Lycka, Antonin,Musilek, Kamil,Prchal, Lukas,Schmidt, Monika,Vinklarova, Lucie,Zemanova, Lucie
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- A aqueous phase preparation 2, 6 - [...] method
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The invention relates to a green preparation 2, 6 - [...] synthetic method, to industrial product is 2, 6 - difluoro-benzamide as the starting material, passes through the aqueous phase Huffman degradation reaction, the aqueous phase diazotisations directly after the hydrolysis, direct concentrated nitric acid nitration, the iron powder reduces the aqueous phase, the aqueous phase with the aqueous phase to diazotization coupling reaction of phenol, after five step process for preparing aqueous phase reactions 2, 6 - [...] production process and corresponding various process conditions. The beneficial effect of the present invention is: select industrialized product 2, 6 - difluoro-benzamide as the raw material, raw materials are easy, low cost, through the aqueous phase reaction and solvent-free reaction for the preparation of 2, 6 - [...], its mild reaction conditions and environmental, safety and high efficiency. The present invention provides a kind of environmental protection, model, high efficiency can be used for the industrial production of 2, 6 - [...] green synthetic pathway.
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- Method for preparing 2,6-difluoroindophenol acetate
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The invention relates to a novel synthetic method for preparing 2,6-difluoroindophenol acetate, in particular to a production process for preparing the 2,6-difluoroindophenol acetate successively by virtue of six reaction steps of industrialized product 2,6-difluorobenzamide serving as a raw material, i.e. Hofmann degradation reaction, diazotization and direct hydrolysis, nitrification with concentrated nitric acid, catalytic hydrogenation reduction with palladium on carbon, diazotization and phenol coupling reaction and esterification under the condition of acetic anhydride and various corresponding process conditions. The method has the beneficial effects that the industrialized product 2,6-difluorobenzamide is used as the raw material, the raw material is easy to obtain, the price is low, and the reaction condition is mild and environmentally friendly. The invention provides a novel efficient way for producing the 2,6-difluoroindophenol acetate in an industrialization manner.
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- CYCLOPROPANE AMIDES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including, but not limited to, malignant melanomas, solid tumors, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocytosis, mast cell leukemia, and diseases caused by PDGFR-α kinase, PDGFR-β kinase, c-KIT kinase, cFMS kinase, c-MET kinase, and oncogenic forms, aberrant fusion proteins and polymorphs of any of the foregoing kinases.
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Page/Page column 68
(2010/05/14)
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- [1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone as a Bioisostere of a Carboxylic Acid Aldose Reductase Inhibitor
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[1-(3,5-Difluoro-4-hydroxyphenyl)-1H-pyrrol-3-yl]phenylmethanone (6) was synthesized as a putative bioisostere of the known aldose reductase (AR) inhibitor (3-benzoylpyrrol-1-yl)acetic acid (I). It was found that 6 is approximately 5 times more potent as
- Nicolaou, Ioannis,Zika, Chariklia,Demopoulos, Vassilis J.
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p. 2706 - 2709
(2007/10/03)
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- 2,6-difluorophenol as a bioisostere of a carboxylic acid: Bioisosteric analogues of γ-aminobutyric acid
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3-(Aminomethyl)-2,6-difluorophenol (6) and 4-(aminomethyl)-2,6- difluorophenol (7) were synthesized in eight and four steps, respectively, starting from 2,6-difluorophenol, to test the potential of the 2,6- difluorophenol moiety to act as a lipophilic bio
- Qiu, Jian,Stevenson, Scott H.,O'Beirne, Michael J.,Silverman, Richard B.
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p. 329 - 332
(2007/10/03)
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- Substituted 4-aminoquinoline derivatives as gastric secretion inhibitors
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Substituted 4-aminoquinazoline derivatives of the formula: STR1 wherein R1 is hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl, phenyl C1-6 alkyl, the phenyl group being optionally substituted; R2 is hydrogen, C1-6 alkyl, C1-6 alkoxy, amino, C1-6 alkylthio, halogen, cyano, hydroxy, C1-6 alkanoyl or trifuromethyl; m is 1 to 3; R3 is hydrogen, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkanoyl, amino, C1-6 alkylamino, ci-C1-6 alkylamino, halogen, trifluoromethyl or cyano; n is 1 or 2; and R4 is hydrogen; or a salt thereof are useful as inhibitors of gastric acid secretion.
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