Delving into the Latest Updates on AEE-788 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

EGFR x HER2 x VEGFR2

Action

antagonists

Mechanism

EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists), HER2 antagonists(Receptor tyrosine-protein kinase erbB-2 antagonists), VEGFR2 antagonists(Vascular endothelial growth factor receptor 2 antagonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Advanced cancerGlioblastoma MultiformeRecurrent Glioblastoma

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

License Organization-

Drug Highest PhasePendingPhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC27H32N6

InChIKeyOONFNUWBHFSNBT-HXUWFJFHSA-N

CAS Registry497839-62-0

AEE788 is an orally active, reversible, small-molecule, multi-targeted kinase inhibitor with potent inhibitory activity against the ErbB and VEGF receptor family of tyrosine kinases. It has an IC50 of less than 100 nM against p-EGFR, p-ErbB2, and p-KDR (VEGFR2). This study will assess the safety, pharmacokinetic/pharmacodynamic (PK/PD) profiles and clinical activity of AEE788 in a recurrent GBM population.

Start Date01 Jan 2004

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT00107237

/ CompletedPhase 1/2

A Phase IB/II Multicenter, Two-Arm, Dose-Escalation Study of Oral AEE788 Administered in Combination With Oral RAD001 on a Continuous Once Daily Dosing Schedule in Adult Patients With First or Second Recurrent or Relapsing Glioblastoma Multiforme

RATIONALE: AEE788 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving AEE788 together with everolimus may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of AEE788 when given together with everolimus and to see how well they work in treating patients with recurrent or relapsed glioblastoma multiforme.

Start Date01 Oct 2003

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

NCT00118456

/ CompletedPhase 1

A Phase I/II, Multicenter, Randomized Dose-Escalation Study of Oral AEE788 on Intermittent Dosing Schedules in Adult Patients With Advanced Cancer (Effective Amendment 5) Previously Entitled A Phase IA, Multicenter, Dose-Escalating Study of Oral AEE788 on a Continuous Daily Dosing Schedule in Adult Patients With Advanced Cancer

AEE788 is an orally active, reversible, small-molecule, multi-targeted kinase inhibitor with potent inhibitory activity against ErbB and VEGF receptor family of tyrosine kinases. It has an IC50 of less than 100 nM against p-EGFR, p-ErbB2, and p-KDR (VEGFR2). This study will assess the safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles and clinical activity of AEE788 in advanced cancers.

Start Date01 Jul 2003

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with AEE-788

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100 Translational Medicine associated with AEE-788

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100 Patents (Medical) associated with AEE-788

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132

Literatures (Medical) associated with AEE-788

07 Jun 2024·The Journal of Organic Chemistry

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

Article

Author: Zhang, Zhuo ; Zheng, Yulong ; Liu, Min ; Li, Hailing ; Qiu, Baojie ; Yuan, Junyu ; Zhang, Xingxian

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. 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.

01 Jan 2024·Chemical Biology & Drug Design

Ligand and structure based hierarchical virtual screening cascade for finding novel epidermal growth factor receptor inhibitors

Article

Author: Sun, Zhiqi ; Huo, Donghui ; Yan, Aixia ; Wang, Maolin

AbstractThe epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand‐based and structure‐based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. 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. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC50 values below 1000 nM. 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.

01 Nov 2023·Anti-Cancer Agents in Medicinal Chemistry

A Combination of EGFR Inhibitors and AE-PDT Could Synergistically Suppress Breast Cancer Progression

Article

Author: Li, Kaiting ; Han, Wang ; Bai, DingQun ; Guo, Xiya ; Tian, Si ; Niu, Yajuan ; Han, Xiaoyu ; Zhu, Ying ; Chen, Qing

Background:Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancerrelated deaths in women. Activation of EGFR by EC-secreted EGFR ligands promotes breast cancer progression. Current treatments provide limited benefits in triple-negative breast cancer (TNBC). Photodynamic therapy (PDT) has been proven effective for the treatment of TNBC through the EGFR pathway, but the underlying mechanism is still unclear.Purpose:The purpose of this study was to determine the role of the EGFR pathway in the treatment of PDT on TNBC in a co-culture system.Methods:MB-231 and HUVEC were co-cultured for experiments (HU-231). Cell viability and ROS production were detected after AE-PDT, a combination of EGFR inhibitors (AEE788)with PDT to test angiogenesis, apoptosis, and pyroptosis. WB detects expression of EGFR. EGFR, P-EGFR, VEGF, caspase-1, capase-3, and GSDMD .Results:AE-PDT inhibited HU-231 cell proliferation and tumor angiogenesis, and induced cell apoptosis and pyroptosis by promoting ROS production. AEE788, an inhibitor of the EGFR, enhanced HU-231 cell killing after AE-PDTConclusion:Our study suggested that the combination of EGFR inhibitors and AE-PDT could synergistically suppress breast cancer progression, providing a new treatment strategy.

100 Deals associated with AEE-788

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External Link

KEGG	Wiki	ATC	Drug Bank
-	AEE-788	-	DB12558

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 Oct 2003
Recurrent Glioblastoma	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 Oct 2003
Advanced cancer	Phase 2	United States	Novartis Pharmaceuticals Corp.	01 Jul 2003

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2007	Phase 1	Colorectal Cancer	22	AEE788	sesajfzlgg(sjnindlyom) = xsfgckpeay cyyczftzwb (aekgkkcdcv ) View more	-	20 Jun 2007
ASCO2005	Phase 1	HR-positive/HER2-low Solid Tumors	69	AEE788	qcscrghxcg(rublavzmdi) = ddrzfbisrq mivozlhoay (xjuhfafdus ) View more	-	01 Jun 2005