225382-62-7Relevant articles and documents
Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors
Aguirre, Enara,Ajenjo, Nuria,Albarran, M. I.,Alvarez, Rosa M.,Blanco-Aparicio, Carmen,Cebria, Antonio,Cebrian, David,Cunningham, Darren,Dave, Harish P. G.,Di Geronimo, Bruno,Garcia, Ana Belen,Gomez-Casero, Elena,Gonzalez Cantalapiedra, Esther,Martin, Jose I.,Martinez-Gonzalez, Sonia,Oneill, Michael,Pastor, Joaquin,Riesco-Fagundo, Concepcion,Rodriguez Hergueta, Antonio,Varela, Carmen
supporting information, p. 1794 - 1801 (2021/11/18)
The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.
A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation
Picado, Alfredo,Chaikuad, Apirat,Wells, Carrow I.,Shrestha, Safal,Zuercher, William J.,Pickett, Julie E.,Kwarcinski, Frank E.,Sinha, Parvathi,De Silva, Chandi S.,Zutshi, Reena,Liu, Shubin,Kannan, Natarajan,Knapp, Stefan,Drewry, David H.,Willson, Timothy M.
, p. 14626 - 14646 (2020/12/23)
STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied "dark"kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.
Identification and SAR of a new series of thieno[3,2-d]pyrimidines as Tpl2 kinase inhibitors
Ni, Yike,Gopalsamy, Ariamala,Cole, Derek,Hu, Yonghan,Denny, Rajiah,Ipek, Manus,Liu, Julie,Lee, Julie,Hall, J. Perry,Luong, Michael,Telliez, Jean-Baptiste,Lin, Lih-Ling
scheme or table, p. 5952 - 5956 (2011/10/18)
We report here the synthesis and SAR of a new series of thieno[3,2-d]pyrimidines as potent Tpl2 kinase inhibitors. The proposed binding mode suggests the potential flipped binding mode depending on the substitution. Biacore studies show evidence of binding of these molecules to the protein kinase. The kinome inhibition profile of these molecules suggests good selectivity.
