1011464-52-0Relevant articles and documents
Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis
Nair, Satheesh,Kumar, Sreekantha Ratna,Paidi, Venkatram Reddy,Sistla, Ramesh,Kantheti, Durgarao,Polimera, Subba Rao,Thangavel, Soodamani,Mukherjee, Amrita Jha,Das, Mitalee,Bhide, Rajeev S.,Pitts, William J.,Murugesan, Natesan,Dudhgoankar, Shailesh,Nagar, Jignesh,Subramani, Siva,Mazumder, Debarati,Carman, Julie A.,Holloway, Deborah A.,Li, Xin,Fereshteh, Mark P.,Ruepp, Stefan,Palanisamy, Kamalavenkatesh,Mariappan, T. Thanga,Maddi, Srinivas,Saxena, Ajay,Elzinga, Paul,Chimalakonda, Anjaneya,Ruan, Qian,Ghosh, Kaushik,Bose, Sucharita,Sack, John,Yan, Chunhong,Kiefer, Susan E.,Xie, Dianlin,Newitt, John A.,Saravanakumar, S. Pon,Rampulla, Richard A.,Barrish, Joel C.,Carter, Percy H.,Hynes, John
, p. 1402 - 1409 (2020)
IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of co
Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation
Zhang, Jing,Fu, Liqiang,Shen, Bin,Liu, Yingtao,Wang, Wenqian,Cai, Xin,Kong, Linglong,Yan, Yilin,Meng, Ryan,Zhang, Zhuming,Chen, Ying-Nan P.,Liu, Qian,Wan, Zhao-Kui,Zhou, Tianyuan,Wang, Xiaotao,Gavine, Paul,Del Rosario, Amanda,Ahn, Kay,Philippar, Ulrike,Attar, Ricardo,Yang, Jennifer,Xu, Yanping,Edwards, James P.,Dai, Xuedong
, p. 1500 - 13,1509 (2020)
The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.Zhang and Fu et al. developed a series of IRAK4 degraders designed from an IRAK4-selective kinase inhibitor to deconvolute IRAK4 kinase and scaffolding functions in ABC DLBCL cells. Interestingly, neither kinase inhibition nor protein degradation affected cell proliferation or apoptosis, suggesting a redundant role of IRAK4 in ABC DLBCL.
Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy
Abid, Mohammad,Alajmi, Mohamed F.,Garrison, Jered,Hasan, Phool,Hussain, Afzal,Imtaiyaz Hassan, Md,Khan, Parvez,King, Hannah M.,Queen, Aarfa,Rana, Sandeep,Rizvi, M. Moshahid Alam,Shamsi, Farheen,Zahid, Muhammad,Zeya, Bushra
, (2020/03/23)
A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 μM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 μM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 μM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 μM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.
