AEE788 / Novartis - LARVOL DELTA

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788. (PubMed, J Org Chem) - "A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788."

Journal

Researches of calcium-activated chloride channel ANO1 intervening amyotrophic lateral sclerosis progression by activating EGFR and CaMKII signaling. (PubMed, Brain Res Bull) - "Our results suggest that ANO1 plays an important role in the survival of ALS motor neurons. ANO1 can increase cell activity and reduce apoptosis by activating EGFR and CaMKII signals."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • ANO1

A Combination of EGFR Inhibitors and AE-PDT Could Synergistically Suppress Breast Cancer Progression. (PubMed, Anticancer Agents Med Chem) - "Our study suggested that the combination of EGFR inhibitors and AE-PDT could synergistically suppress breast cancer progression, providing a new treatment strategy."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Ligand and structure based hierarchical virtual screening cascade for finding novel epidermal growth factor receptor inhibitors. (PubMed, Chem Biol Drug Des) - "We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K-means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds."

Journal • Oncology • EGFR

Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer. (PubMed, J Mol Model) - "The compound AEE788 displays great affinity towards the target protein as a result of docking study...Based on molecular dynamics simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 has a high affinity with the lowest re-rank score and holds a huge potential to inhibit the VGFR and can be implemented for prospective future investigations in ovarian cancer."

Journal • Oncology • Ovarian Cancer • Solid Tumor

Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer (AACR 2018) - "ChEMBL-based cheminformatics analysis indicated that, besides VEGFR and EGFR, a number of other kinases were predicted as the targets of AEE788, including RPS6K1, AKT2 and CDK7. Altogether, our data reveals the essential role of rapamycin-associated translation factors in TNBC, and provides insight in the resistance of TNBC to rapamycin analogues as well as potential therapeutic approaches to alleviate rapamycin resistance."

Triple Negative Breast Cancer

New targeted therapies for anaplastic thyroid cancer (Anticancer Agents Med Chem) - Tyrosine kinases inhibitors are actually under evaluation for the treatment of anaplastic thyroid cancer (ATC), for example imanitib or sorafenib; These agents include: combretastatin A4 phosphate, aplidin, PTK787/ZK222584, & human VEGF monoclonal antibodies (bevacizumab, cetuximab); Small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at EGFR's tyrosine kinase, such as erlotinib, or gefitinib are also under evaluation; Preclinical study evaluated the activity of a dual inhibitor of EGFR & VEGF, NVP-AEE788, alone & in combination with paclitaxel for the treatment of ATC

Review • Oncology

AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells (Life Sci) - Increased reactive oxygen generation, loss of mitochondrial membrane potential, cleavage of PARP, caspase-3 activation & DNA ladder formation characterized the induction of apoptosis by celecoxib &/or AEE788 treatment; Either drug individually induced apoptosis via down-regulation of the anti-apoptotic proteins Bcl(2) & Bcl-x(L), & up-regulation of pro-apoptotic protein Bax, cleavage of PARP, activation of caspase-3 & inhibition of vascular endothelial growth factor receptor signaling pathways

Preclinical • Oncology

Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib (PLoS One) - Both lapatinib-sensitive & lapatinib-resistant ERBB2 mutations were observed; Resistance mutations may also cause secondary in cloned cell lines with clinically observed ERBB2 mutations resistance in lapatinib-treated pts; Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 & WZ-4002

Preclinical-other • Breast Cancer • Oncology

The combination of multiple receptor tyrosine kinase inhibitor and mTOR inhibitor overcomes erlotinib-resistant lung cancer cell line through c-Met inhibition (Mol Cancer Res) -

AEE788 inhibited the cell growth more effectively than erlotinib in the three NSCLC cell lines examined; In the EGFR-TKI resistant cell line harboring T790M resistant mutation, cell growth inhibition by AEE788 was only mild; In H1975, AEE788 induced significant cell growth inhibition when combined with RAD001 compared to when used alone; This cooperative effect was not seen in the combination of erlotinib with RAD001

Cyclooxygenase-2 inhibition enhances the anti-tumoral activity of the multi-target kinase inhibitor AEE788 in colorectal cancer cells (ESMO 2012) - Presentation time: September 30, 2012; 1:00 PM - 2:00 PM; AEE788 reduced in Caco-2 cells both VEGF production & VEGF-dependent growth, effects that were associated with the inhibition of ERK1/2 phosphorylation & the increased expression of COX-2 observed in these cells

Colorectal Cancer • Oncology

Anti-tumoral effects of the multi-targeted kinase inhibitor AEE788 in BRAF mutated colorectal cancer cells (EORTC-NCI-AACR 2010) -

Results support that AEE788 may be effective in the management of colorectal cancer in a non-mutated KRAS setting, independently of BRAF mutational status

AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome. (PubMed) - Mol Pharmacol - "Putative effectors include an SR protein kinase, bilobe proteins, TbSAS4, TbRP2, and BILBO-1. Loss of function of one or more of these effectors can, from published literature, explain the polypharmacology of AEE788 on trypanosome biology."

Journal • Biosimilar

Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients (Cancer Chemother Pharmacol) - P1, N=64; CAEE788A2103; Two Grp A pts experienced DLTs (proteinuria & stomatitis) at 550 mg; One Grp B pt receiving 800 mg experienced a DLT (diarrhea); Best overall response was SD (17%)

P1 data • Oncology

Using pharmacokinetic and pharmacodynamic data in decision making regarding drug development: a phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788 (Clin Cancer Res) - P1, N=111; Study id: CAEE788A2101; MTD was 450 mg/day; Effects on biomarkers correlated to serum AEE788 concentrations; No inhibition of p-MAPK & Ki67 was observed in skin vessels at ≤ MTD; AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD; A total of 16/96 evaluable pts demonstrated a > 10% shrinkage of tumor size; One PR was observed

P1 data • Oncology

Pharmacokinetic drug interaction between AEE788 and RAD001 causing thrombocytopenia in patients with glioblastoma (Cancer Chemother Pharmacol) - P1b/2, N=16; UCLA-0409004-01; All pts discontinued the study most commonly because of disease progression; Four pts experienced DLT; Both pts receiving AEE788 (200 mg/day) plus RAD001 (5 mg/day) experienced clinically significant thrombocytopenia requiring a dose reduction/interruption; AEE788 appeared to inhibit the metabolism of RAD001; The study was terminated prematurely before an MTD was determined because of safety findings in other studies evaluating AEE788 monotherapy

P1/2 data • Oncology

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer. (PubMed, Breast Cancer Res Treat) - "mTOR signaling is highly activated in TNBC tumors. As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, our results thus provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in TNBC cells."

Journal

Brain distribution of a panel of EGFR inhibitors using cassette-dosing in wild-type and Abcb1/Abcg2 deficient mice. (PubMed, Drug Metab Dispos) - "To identify optimal compounds for brain delivery, eight EGFR inhibitors [afatinib, 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-(1-phenylethyl)-7H-pyrrolo[2,3-day]pyrimidin-4-amine (AEE788), [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2R)-2,4-dimethylpiperazine-1-carboxylate (AZD3759), erlotinib, dacomitinib, gefitinib, osimertinib, and vandetanib] were evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency,..."

Journal • Preclinical

Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer. (PubMed, Comput Biol Chem) - "In the current study, the direct binding of three wild type-selective inhibitors (Lapatinib, AEE788 and TAK-285) and two wild type-sparing inhibitors (Staurosporine and Bosutinib) to the wild-type ErbB2 and its T798M mutant are investigated in detail by using rigorous computational analysis and binding affinity assay. The binding affinity of Staurosporine and Bosutinib to ErbB2 kinase domain is improved by 11.9-fold and 2.1-fold upon T798M mutation, respectively. Structural analysis reveals that a nonbonded network of S-π contact interactions (for Staurosporine) or an S-involving halogen bond (for Bosutinib) forms with the sulfide group of mutant Met798 residue."

Journal