Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker

Abstract

Deregulation of the ErbB (proto-oncogene B of the avian erythroblastosis virus AEV-H strain) receptor network is well recognized as an oncogenic driver in epithelial cancers. Several targeted drugs have been developed, including antibodies and small-molecule kinase inhibitors, each of them characterized by distinct patterns of ErbB receptor interactions. Understanding the precise pharmacological properties of these compounds is important for optimal use in clinical practice. Afatinib [BIBW 2992; N-[4-[(3-chloro-4-is an ATP-competitive anilinoquinazoline derivative harboring a reactive acrylamide group. It was designed to covalently bind and irreversibly block enzymatically active ErbB receptor family members. Here, we show by X-ray crystallography the covalent binding of afatinib to wild-type epidermal growth factor receptor (EGFR) and by mass spectrometry the covalent interaction with EGFR, EGFR L858R/T790M , human epidermal growth factor receptor 2 (HER2), and ErbB-4. Afatinib potently inhibits the enymatic activity of ErbB-4 (EC 50 ϭ 1 nM) and the proliferation of cancer cell lines driven by multiple ErbB receptor aberrations at concentrations below 100 nM., a close analog of afatinib lacking the acrylamide group and thus incapable of covalent bond formation, had similar potency on cells driven by EGFR or EGFR L858R , but less or no detectable activity on cells expressing EGFR L858R/ T790M HER2 or ErbB-4. These results stress the importance of the acrylamide group and show that afatinib differs from approved ErbB targeting agents by irreversibly inhibiting the kinase activity of all ErbB family members. They provide a mechanistic rationale for the distinct pharmacological features of this compound and explain the clinical activity seen in some patients who are resistant to antibody or kinase inhibitor therapy because of secondary mutations or ErbB receptor "reprogramming."

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial

“…Выраженность и продолжитель-ность ответа также оказались лучше при лечении афати-нибом. Улучшение противоопухолевой активности при лечении афатинибом может отражать его более сильное и необратимое ингибирование путей передачи сигнала EGFR [26,27]. Частота объективного ответа, наблюдавша-яся при лечении афатинибом (70%) в этом исследовании, соответствовала результатам исследований LUX-Lung 3 и LUX-Lung 6 (61 и 67% соответственно у пациентов с рас-пространенными мутациями EGFR) [28,29].…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…Afatinib is an oral, irreversible PanHER family blocker, which selectively and potently blocks signaling from the 3 catalytically active HER-family receptors, and also inhibits transphosphorylation of the inactive member, HER3/ ERBB3. 22 In lung cancer patients with EGFR mutations, afatinib has been associated with prolonged progression-free survival, compared to chemotherapy. This led to approval of oral afatinib, in 2013, for the first-line treatment of patients with metastatic NSCLC who have tumors with EGFR mutations.…”

“…94 Among these, dacomitinib and afatinib. 22 are particularly well advanced, and they possess novel features, such as irreversible binding to the target receptors and prevention of downstream signals. However, it has not been clearly documented in the clinic that panHER TKIs directly impact HER3 function.…”

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…i) The EGF receptor antagonists (149)(150)(151)(152)(153)(154)(155)(156) iii) The CXCR receptor antagonist (76,77,161,162), AMD070 [Log OWPC, -0.14; vdWD: 0.85 nm; Log OWPC-to-vdWD ratio, -0. (170) results in decreased mitogenesis and cell division, while the decrease in the transcription of the lower MW protein forms including VEGF (20 kDa) necessary for autocrine angiogenesis (154,171), and importantly, BCL (26 kDa) necessary for maintenance of MM integrity in tumor cells (BCL-dependent) (59), results in increased mitochondria-mediated apoptosis, particularly in p53-deficient tumor cells (172)(173)(174) (Table XI and Fig.…”