612501-81-2Relevant articles and documents
Design of a "two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites
Wittlinger, Florian,Heppner, David E.,To, Ciric,Günther, Marcel,Shin, Bo Hee,Rana, Jaimin K.,Schmoker, Anna M.,Beyett, Tyler S.,Berger, Lena M.,Berger, Benedict-Tilman,Bauer, Nicolas,Vasta, James D.,Corona, Cesear R.,Robers, Matthew B.,Knapp, Stefan,J?nne, Pasi A.,Eck, Michael J.,Laufer, Stefan A.
supporting information, p. 1370 - 1383 (2021/11/13)
Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
Discovery of AZD8931, an equipotent, reversible inhibitor of signaling by EGFR, HER2, and HER3 receptors
Barlaam, Bernard,Anderton, Judith,Ballard, Peter,Bradbury, Robert H.,Hennequin, Laurent F. A.,Hickinson, D. Mark,Kettle, Jason G.,Kirk, George,Klinowska, Teresa,Lambert-Van Der Brempt, Christine,Trigwell, Cath,Vincent, John,Ogilvie, Donald
, p. 742 - 746 (2013/09/02)
Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.
Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics
Ballard, Peter,Bradbury, Robert H.,Harris, Craig S.,Hennequin, Laurent F.A.,Hickinson, Mark,Kettle, Jason G.,Kendrew, Jane,Klinowska, Teresa,Ogilvie, Donald J.,Pearson, Stuart E.,Williams, Emma J.,Wilson, Ingrid
, p. 4908 - 4912 (2008/09/21)
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.
