123045-62-5Relevant academic research and scientific papers
Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods
Sarkar, Dhruba,Olejniczak, Edward T.,Phan, Jason,Coker, Jesse A.,Sai, Jiqing,Arnold, Allison,Beesetty, Yugandhar,Waterson, Alex G.,Fesik, Stephen W.
, p. 8325 - 8337 (2020/09/21)
The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2
Conlon, Ivie L.,Drennen, Brandon,Lanning, Maryanna E.,Hughes, Samuel,Rothhaas, Rebecca,Wilder, Paul T.,MacKerell, Alexander D.,Fletcher, Steven
supporting information, p. 1691 - 1698 (2020/07/04)
Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.
SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-xL and Mcl-1
Rega, Michele F.,Wu, Bainan,Wei, Jun,Zhang, Ziming,Cellitti, Jason F.,Pellecchia, Maurizio
supporting information; experimental part, p. 6000 - 6013 (2011/10/09)
Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl-xL and Mfl-1, has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted
PYRAZOLYL ACYLSULFONAMIDE DERIVATIVES AS ENDOTHELIN CONVERTING ENZYME INHIBITORS AND USEFUL IN THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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Page/Page column 61-62, (2008/06/13)
The invention provides compounds of formula (I),wherein R?1?,R?2? ,R?3? and R?4? are as defined in the specification,processes for preparing such compounds,to pharmaceutical compositions comprising such compounds and to the use of the compounds as active
