8D73

Crystal Structure of EGFR LRTM with compound 7

Summary for 8D73

• Entry DOI: 10.2210/pdb8d73/pdb
• Descriptor: Epidermal growth factor receptor, GLYCEROL, (3S,4R)-3-fluoro-1-(4-{[4-(methylamino)-1-(propan-2-yl)pyrido[3,4-d]pyridazin-7-yl]amino}pyrimidin-2-yl)piperidin-4-ol, ... (4 entities in total)
• Functional Keywords: protein kinase, inhibitor, kinase domain, mutation, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 80604.67

Authors

Kim, J.L. (deposition date: 2022-06-07, release date: 2022-07-27, Last modification date: 2023-10-18)

Primary citation

Eno, M.S.,Brubaker, J.D.,Campbell, J.E.,De Savi, C.,Guzi, T.J.,Williams, B.D.,Wilson, D.,Wilson, K.,Brooijmans, N.,Kim, J.,Ozen, A.,Perola, E.,Hsieh, J.,Brown, V.,Fetalvero, K.,Garner, A.,Zhang, Z.,Stevison, F.,Woessner, R.,Singh, J.,Timsit, Y.,Kinkema, C.,Medendorp, C.,Lee, C.,Albayya, F.,Zalutskaya, A.,Schalm, S.,Dineen, T.A.
Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.
J.Med.Chem., 65:9662-9677, 2022

PubMed Abstract: While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound ) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

PubMed: 35838760
DOI: 10.1021/acs.jmedchem.2c00704

Experimental method

X-RAY DIFFRACTION (2.17 Å)