- Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer
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Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.
- Lücking, Ulrich,Kosemund, Dirk,B?hnke, Niels,Lienau, Philip,Siemeister, Gerhard,Denner, Karsten,Bohlmann, Rolf,Briem, Hans,Terebesi, Ildiko,B?mer, Ulf,Sch?fer, Martina,Ince, Stuart,Mumberg, Dominik,Scholz, Arne,Izumi, Raquel,Hwang, Stuart,Von Nussbaum, Franz
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p. 11651 - 11674
(2021/07/31)
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- 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
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Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
- Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
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supporting information
p. 707 - 731
(2020/08/24)
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- Aniline pyrimidines, its preparation method and medical use (by machine translation)
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The invention relates to: an aniline pyrimidine compound represented as the formula (I), a medicinal salt thereof, a prodrug thereof, and a hydrate or solvate thereof and also relates to: the preparation method of the compound, a medicine composition comp
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Paragraph 0189; 0190; 0191
(2018/03/01)
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- Identification of Atuveciclib (BAY 1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer
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Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.
- Lücking, Ulrich,Scholz, Arne,Lienau, Philip,Siemeister, Gerhard,Kosemund, Dirk,Bohlmann, Rolf,Briem, Hans,Terebesi, Ildiko,Meyer, Kirstin,Prelle, Katja,Denner, Karsten,B?mer, Ulf,Sch?fer, Martina,Eis, Knut,Valencia, Ray,Ince, Stuart,von Nussbaum, Franz,Mumberg, Dominik,Ziegelbauer, Karl,Klebl, Bert,Choidas, Axel,Nussbaumer, Peter,Baumann, Matthias,Schultz-Fademrecht, Carsten,Rühter, Gerd,Eickhoff, Jan,Brands, Michael
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p. 1776 - 1793
(2017/10/23)
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- FLUORINATED BENZOFURANYL-PYRIMIDINE DERIVATIVES CONTAINING A SULFONE GROUP
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The present invention relates to fluorinated benzofuranyl-pyrimidine derivatives containing a sulfone group of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disord
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Page/Page column 53
(2016/05/24)
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- METHODS FOR INHIBITING NECROPTOSIS
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The present invention relates to methods for inhibiting necroptosis; screening methods for identifying compounds which inhibit necroptosis; and compounds for the inhibition of necroptosis, which may be useful in the treatment of conditions associated with deregulated necroptosis.
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Page/Page column 115; 116
(2015/12/30)
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- PYRIDINE CDK9 KINASE INHIBITORS
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Disclosed are compound of Formula (Ia), wherein R2, R12, R16, J, Q, X, Y and Z are as defined in the specification, and pharmaceutically acceptable salts thereof.The compounds may be used as agents in the treatment of diseases, including cancer. Also provided are pharmaceutical compositions comprising one or more compounds of Formula (Ia).
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Paragraph 1978
(2014/09/29)
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- DISUBSTITUTED 5-FLUORO-PYRIMIDINES
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The present invention relates to disubstituted 5-fluoro-pyrimidines of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferativ
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Page/Page column 68
(2013/03/28)
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- 2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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Page/Page column 151-152
(2012/05/20)
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- SUBSTITUTED 4-ARYL-N-PHENYL-1,3,5-TRIAZIN-2-AMINES
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The present invention relates to substituted 4-Aryl-N-phenyl-1,3,5-triazin-2-amines of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hy
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Page/Page column 74
(2012/11/07)
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- INHIBITORS OF PROTEIN KINASES
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The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
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Page/Page column 147
(2009/12/05)
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- 4, 6-DISUBSTITUTED AMINOPYRIMIDINE DERIVATIVES AS INHIBITORS OF PROTEIN KINASES
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The present invention relates to inhibitors of general Formula (I) of cyclin-dependent kinases and therapeutic applications thereof. Furthermore, the invention relates to compounds for preventing and/or treating any type of pain, inflammatory disorders, immunological diseases, proliferative diseases, infectious diseases, cardiovascular diseases and neurodegenerative diseases.
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Page/Page column 154-155; 174
(2008/12/08)
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- Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase
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A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.
- Sammond, Douglas M.,Nailor, Kristen E.,Veal, James M.,Nolte, Robert T.,Wang, Liping,Knick, Victoria B.,Rudolph, Sharon K.,Truesdale, Anne T.,Nartey, Eldridge N.,Stafford, Jeffrey A.,Kumar, Rakesh,Cheung, Mui
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p. 3519 - 3523
(2007/10/03)
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- Azetidine derivatives, their preparation and medicaments containing them
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The invention concerns compounds of formula (1) wherein: R represents a chain (A) or (B); R1 is methyl or ethyl; R2 is either an optionally substituted aromatic or an optionally substituted heteroaromatic ring; R3 and R4, identical or different, are either an optionally substituted aromatic or an optionally substituted heteroaromatic ring; R′ represents a hydrogen atom or a —CO—alk radical, their optical isomers, their salts, their preparation and medicines containing them.
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- Azetidine derivatives, their preparation and pharmaceutical compositions containing them
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Compounds of formula: in which R represents a CR1R2, C═C(R5)SO2R6 or C═C(R7)SO2alk radical, their preparation and the pharmaceutical compositions containing them.
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