In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14718-e14718
Abstract:
e14718 Background: The majority of EGFR mutant tumors can be effectively treated with targeted drugs. Lung adenocarcinoma patients with EGFR Ex20 insertion mutations, however, lack safe and potent treatment options. These genetic alterations share homology with HER2 Ex20 insertion mutations and perturb the ATP binding pocket in a way that limits accessibility through currently available tyrosine kinase inhibitors. Second-generation EGFR inhibitors are partially active in EGFR Ex20 mutant models but their potent activity against wild type (WT) EGFR and the resulting adverse effects largely prohibit the clinical use of these drugs. To address this medical need, we developed PRB001, a novel EGFR kinase inhibitor. Methods: We facilitated protein X-ray crystallography to guide the development of small molecule inhibitors with high potency against EGFR/HER2 Ex20 mutant kinases and low activity against WT EGFR. Iterative compound optimization involved biochemical profiling concerning inhibition and binding kinetics, cellular profiling as well as mouse pharmacokinetic and mouse efficacy studies. Results: PRB001 exhibits potent activity against EGFR/HER2 Ex20 insertion mutations, in genetically engineered Ba/F3 cell line models and patient derived cell lines. At the same time, PRB001 exhibits a 10-100 fold lower activity against WT EGFR in several cellular models. Our data indicate that PRB001 and its derivatives display a therapeutic window for an effective treatment of EGFR Ex20 mutant tumors with a limited toxicity profile. Mouse xenograft experiments support these results, showing that, in contrast to second-generation EGFR inhibitors, PRB001 does not inhibit WT EGFR and does not lead to loss of weight of treated animals at effective doses of 90 mg/kg daily. Conclusions: Our data support the notion that PRB001 effectively kills a wide range of EGFR Ex20 mutant cellular models and together with its safety profile builds a basis for the development of a mutant-selective and clinically effective tyrosine kinase inhibitor.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2019.37.15_suppl.e14718
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2019
detail.hit.zdb_id:
2005181-5
detail.hit.zdb_id:
604914-X
Permalink
