- Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13
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Genetic depletion of cyclin-dependent kinase 12 (CDK12) or selective inhibition of an analog-sensitive CDK12 reduces DNA damage repair gene expression, but selective inhibition of endogenous CDK12 is difficult. Here, we report the development of MFH290, a novel cysteine (Cys)-directed covalent inhibitor of CDK12/13. MFH290 forms a covalent bond with Cys-1039 of CDK12, exhibits excellent kinome selectivity, inhibits the phosphorylation of serine-2 in the C-terminal domain (CTD) of RNA-polymerase II (Pol II), and reduces the expression of key DNA damage repair genes. Importantly, these effects were demonstrated to be CDK12-dependent as mutation of Cys-1039 rendered the kinase refractory to MFH290 and restored Pol II CTD phosphorylation and DNA damage repair gene expression. Consistent with its effect on DNA damage repair gene expression, MFH290 augments the antiproliferative effect of the PARP inhibitor olaparib.
- Liu, Yao,Hao, Mingfeng,Leggett, Alan L.,Gao, Yang,Ficarro, Scott B.,Che, Jianwei,He, Zhixiang,Olson, Calla M.,Marto, Jarrod A.,Kwiatkowski, Nicholas P.,Zhang, Tinghu,Gray, Nathanael S.
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p. 6708 - 6726
(2020/09/11)
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- Metal-Free One-Pot Chemoselective Thiocyanation of Imidazothiazoles and 2-Aminothiazoles with in situ Generated N-Thiocyanatosuccinimide
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A chemoselective thiocyanation of imidazothiazoles and 2-aminothiazoles with use of in situ generated N-thiocyanatosuccinimide (NTS) at room temperature is described. The protocol offers mild reaction conditions and high chemoselectivity for electrophilic substitution in imidazothiazoles over nucleophilic substitution. This method provides metal-free and easy conversion of imidazothiazoles and 2-aminothiazoles into their corresponding C-3 and C-5 thiocyanates, respectively, in good to excellent yield. The present protocol also offers the effective thiocyanation of bifunctional imidazothiazoles containing aliphatic -OH and C(sp 2)-H bond functionalities.
- Kadam, Shuddhodan N.,Ambhore, Ajay N.,Hebade, Madhav J.,Kamble, Rahul D.,Hese, Shrikant V.,Gaikwad, Milind V.,Gavhane, Priya D.,Dawane, Bhaskar S.
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p. 1902 - 1908
(2018/08/28)
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- INHIBITORS OF CYCLIN-DEPENDENT KINASES
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The present invention provides novel compounds of Formulae (I'), (I), (II'), and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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Paragraph 00325; 00505; 00468
(2017/04/28)
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- CDK INHIBITORS
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The present invention relates to CDK inhibitors and their use in the treatment of cell proliferative diseases such as cancer.
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Page/Page column 52
(2010/07/09)
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- CDK INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to CDK inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The compounds of the invention may further act as HDAC inhibitors.
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Page/Page column 54
(2009/04/25)
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- UREA GLUCOKINASE ACTIVATORS
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This application relates to novel urea glucokinase activators and use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes. Further encompassed is a pharmaceutic
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Page/Page column 45
(2008/12/07)
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- UREA GLUCOKINASE ACTIVATORS
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This application relates to novel urea glucokinase activators and use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e.g. for the treatment of type 2 diabetes. Further encompassed is a pharmaceutic
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Page/Page column 60
(2008/12/07)
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- NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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Compounds are provided which are glucokinase activators and thus are useful in treating diabetes and related diseases and have the structure wherein in the ring represents one or two double bonds; R1 is aryl or heteroaryl; R2 is halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is as defined herein; Z is O, S, S(O), S(O)2, or NR5a; X is S, O, N, NR3, or CR3; Y is NCR4 or N4; R3, R4, and R5 are as defined herein; R8 is aryl or heteroaryl; R6 and R7 are independently H, halogen, or alkyl; m is 0 or 1; and n is 0 to 3, or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
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Page/Page column 25
(2008/06/13)
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- NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
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Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R4 is —(CH2)n-Z-(CH2)m—PO(OR7)(OR8), —(CH2)nZ-(CH2)m—PO(OR7)Rg, —(CH2)n-Z-(CH2)m—OPO(OR7)Rg, —(CH2)nZ—(CH2)m—OPO(R9)(R10), or —(CH2)nZ—(CH2)m—PO(R9)(R10);R5 and R6 are independently selected from H, alkyl and halogen;Y is R7(CH2)s or is absent; andX, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.
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Page/Page column 48-49
(2008/06/13)
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- UREA GLUCOKINASE ACTIVATORS
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The invention provides a compound of general formula (I) wherein the substituents are defined futher in the application, as well as further embodiments hereof described in the attached embodiments. The present invention also provides use of the compounds
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Page/Page column 93; 156
(2008/06/13)
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- N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl] -4-piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent
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N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyl]m
- Misra, Raj N.,Xiao, Hai-Yun,Kim, Kyoung S.,Lu, Songfeng,Han, Wen-Ching,Barbosa, Stephanie A.,Hunt, John T.,Rawlins, David B.,Shan, Weifang,Ahmed, Syed Z.,Qian, Ligang,Chen, Bang-Chi,Zhao, Rulin,Bednarz, Mark S.,Kellar, Kristen A.,Mulheron, Janet G.,Batorsky, Roberta,Roongta, Urvashi,Kamath, Amrita,Marathe, Punit,Ranadive, Sunanda A.,Sack, John S.,Tokarski, John S.,Pavletich, Nikola P.,Lee, Francis Y. F.,Webster, Kevin R.,Kimball, S. David
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p. 1719 - 1728
(2007/10/03)
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- Aminothiazole inhibitors of cyclin dependent kinases
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Compounds of the formula and pharmaceutically acceptable salts thereof. R1and R2are independently hydrogen, fluorine or alkyl; R3is aryl or heteroaryl R4is alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, he
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- Aminothiazole inhibitors of cyclin dependent kinases
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Compounds of the formula and pharmaceuticaly acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings: R1 and R2 are independently hydrogen, fluorine or alkyl; R3 is aryl or heteroaryl R4 is
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- Method and composition for the prevention, control and amelioration of soilborne fungi and disease caused thereby
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Methods and compositions utilizing 2-amino-5-thiazolyl thiocyanate compounds and their derivatives for the control of soilborne fungi and disease caused thereby are described.
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