192189-18-7Relevant articles and documents
Discovery of Potent, Selective, and Brain-Penetrant 1 H-Pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors
Fushimi, Makoto,Fujimori, Ikuo,Wakabayashi, Takeshi,Hasui, Tomoaki,Kawakita, Youichi,Imamura, Keisuke,Kato, Tomoko,Murakami, Morio,Ishii, Tsuyoshi,Kikko, Yorifumi,Kasahara, Maki,Nakatani, Atsushi,Hiura, Yuto,Miyamoto, Maki,Saikatendu, Kumar,Zou, Hua,Lane, Scott Weston,Lawson, J. David,Imoto, Hiroshi
, p. 4915 - 4935 (2019/05/22)
Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is s
Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent in Vitro and in Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
Singh, Umed,Chashoo, Gousia,Khan, Sameer U.,Mahajan, Priya,Nargotra, Amit,Mahajan, Girish,Singh, Amarinder,Sharma, Anjna,Mintoo, Mubashir J.,Guru, Santosh Kumar,Aruri, Hariprasad,Thatikonda, Thanusha,Sahu, Promod,Chibber, Pankaj,Kumar, Vikas,Mir, Sameer A.,Bharate, Sonali S.,Madishetti, Sreedhar,Nandi, Utpal,Singh, Gurdarshan,Mondhe, Dilip Manikrao,Bhushan, Shashi,Malik, Fayaz,Mignani, Serge,Vishwakarma, Ram A.,Singh, Parvinder Pal
, p. 9470 - 9489 (2017/12/26)
In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ～33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.
Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors via one-pot Sonogashira coupling-TMS-deprotection-CuAAC sequence
Merkul, Eugen,Klukas, Fabian,Dorsch, Dieter,Graedler, Ulrich,Greiner, Hartmut E.,Mueller, Thomas J. J.
supporting information; experimental part, p. 5129 - 5136 (2011/09/13)
The one-pot, three-component Sonogashira coupling-TMS-deprotection-CuAAC ("click") sequence is the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the development of more active derivatives. The X-ray structure analysis of compound 8f in complex with PDK1 has revealed the detailed binding mode of the molecule in the kinase. The Royal Society of Chemistry 2011.
