875639-15-9Relevant articles and documents
Discovery of a series of 1H-pyrrolo[2,3-b]pyridine compounds as potent TNIK inhibitors
Yang, Bowen,Wu, Qian,Huan, Xiajuan,Wang, Yingqing,Sun, Yin,Yang, Yueyue,Liu, Tongchao,Wang, Xin,Chen, Lin,Xiong, Bing,Zhao, Dongmei,Miao, Zehong,Chen, Danqi
, (2020/12/28)
In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC50 values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.
Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
Klug, Dana M.,Mavrogiannaki, Eftychia M.,Forbes, Katherine C.,Silva, Lisseth,Diaz-Gonzalez, Rosario,Pérez-Moreno, Guiomar,Ceballos-Pérez, Gloria,Garcia-Hernández, Raquel,Bosch-Navarrete, Cristina,Cordón-Obras, Carlos,Gómez-Li?án, Claudia,Saura, Andreu,Momper, Jeremiah D.,Martinez-Martinez, Maria Santos,Manzano, Pilar,Syed, Ali,El-Sakkary, Nelly,Caffrey, Conor R.,Gamarro, Francisco,Ruiz-Perez, Luis Miguel,Gonzalez Pacanowska, Dolores,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
, p. 9404 - 9430 (2021/07/25)
Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.
From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement
Mostinski, Yelena,Heynen, Guus J. J. E.,López-Alberca, Maria Pascual,Paul, Jerome,Miksche, Sandra,Radetzki, Silke,Schaller, David,Shanina, Elena,Seyffarth, Carola,Kolomeets, Yuliya,Ziebart, Nandor,De Schryver, Judith,Oestreich, Sylvia,Neuenschwander, Martin,Roske, Yvette,Heinemann, Udo,Rademacher, Christoph,Volkamer, Andrea,Von Kries, Jens Peter,Birchmeier, Walter,Nazaré, Marc
, p. 14780 - 14804 (2020/12/23)
The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC50 = 0.031 μM in an enzymatic assay and with an IC50 = 2.6 μM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.
