Delving into the Latest Updates on AZD-3229 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

PDGFRα x c-Kit

Mechanism

PDGFRα inhibitors(Platelet-derived growth factor receptor alpha inhibitors), c-Kit inhibitors(Stem cell growth factor receptor inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Advanced cancerAdvanced Malignant Solid NeoplasmGastrointestinal Stromal Tumors+ [1]

Inactive Indication-

Originator Organization

AstraZeneca PLC

Active Organization

Ningbo Taikang Pharmaceutical Technology Co. Ltd.Ningbo Xinwan Pharmaceutical Technology Co., Ltd.

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC24H26FN7O3

InChIKeyFLJOFQUXYAWOPE-UHFFFAOYSA-N

CAS Registry2248003-60-1

Part 1 ：食物影响研究主要目的：在健康受试者中评价食物对NB003片单次给药药代动力学的影响。次要目的：在健康受试者中评价NB003片空腹/餐后状态下单次给药的安全性和耐受性。 Part 2 ：与奥美拉唑相互作用研究主要目的：在健康受试者中评价奥美拉唑镁肠溶片多次给药对NB003片单次给药药代动力学的影响。次要目的:在健康受试者中评价NB003片单次给药及与奥美拉唑镁肠溶片联合给药的安全性和耐受性。

[Translation]

Part 1: Food effect study Primary objective: To evaluate the effect of food on the pharmacokinetics of a single dose of NB003 tablets in healthy subjects. Secondary objective: To evaluate the safety and tolerability of a single dose of NB003 tablets in fasting/fed state in healthy subjects. Part 2: Interaction study with omeprazole Primary objective: To evaluate the effect of multiple doses of omeprazole magnesium enteric-coated tablets on the pharmacokinetics of a single dose of NB003 tablets in healthy subjects. Secondary objective: To evaluate the safety and tolerability of a single dose of NB003 tablets and co-administration with omeprazole magnesium enteric-coated tablets in healthy subjects.

Start Date-

Sponsor / Collaborator

Ningbo Taikang Pharmaceutical Technology Co. Ltd.

NCT04936178 / RecruitingPhase 1

A Multicenter Phase 1, Open-Label Study of NB003 to Assess Safety, Tolerability, Pharmacokinetics and Efficacy in Patients With Advanced Malignancies

This a A Phase 1, Open-label, Multicenter Study to Assess the Safety, Tolerability, and Pharmacokinetics of NB003 in Subjects with Advanced Malignancies

Start Date06 Aug 2021

Sponsor / Collaborator

Ningbo Xinwan Pharmaceutical Technology Co., Ltd.

100 Clinical Results associated with AZD-3229

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100 Translational Medicine associated with AZD-3229

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100 Patents (Medical) associated with AZD-3229

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3

Literatures (Medical) associated with AZD-3229

15 Jul 2020·Clinical Cancer ResearchQ1 · MEDICINE

The Pharmacokinetic–Pharmacodynamic (PKPD) Relationships of AZD3229, a Novel and Selective Inhibitor of KIT, in a Range of Mouse Xenograft Models of GIST

Q1 · MEDICINE

Article

Author: Kettle, Jason G. ; Guichard, Sylvie M. ; Smith, Aaron ; Jones, Rhys D.O. ; Banks, Erica ; Barry, Evan ; Brown, Crystal ; Pilla Reddy, Venkatesh ; Grondine, Michael ; Shao, Wenlin ; Bhavsar, Deepa ; Anjum, Rana

AbstractPurpose:The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.Experimental Design:A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several in vivo preclinical tumor models, and in vitro data generated in a panel of Ba/F3 cell lines.Results:AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.Conclusions:We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.

29 Apr 2020·Science Translational MedicineQ1 · MEDICINE

Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors

Q1 · MEDICINE

Article

Author: Reddy, Venkatesh Pilla ; Shao, Wenlin ; Banks, Erica ; Jones, Rhys DO. ; Collins, Teresa ; Harmer, Alexander R. ; Lawson, Deborah ; Packer, Martin J. ; Wang, Haiyun ; Drew, Lisa ; Mettetal, Jerome T. ; Wilson, David ; Adeyemi, Oladipupo ; Anjum, Rana ; Overman, Ross ; Cosulich, Sabina ; Guichard, Sylvie ; Barry, Evan ; Grondine, Michael ; Brown, Crystal ; Reimer, Corinne ; Kettle, Jason G. ; Bhavsar, Deepa ; Fawell, Stephen

AZD3229 demonstrates pan-KIT/PDGFRα activity in several preclinical models and is a promising agent for the treatment of GIST.

11 Oct 2018·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors

Q1 · MEDICINE

Article

Author: Schimpl, Marianne ; Shao, Wenlin ; Boyd, Scott ; Li, Xiuwei ; Barry, Evan ; Pearson, Stuart ; Overman, Ross C. ; Goldberg, Kristin ; Moleva, Olga ; Anjum, Rana ; Hardy, Christopher J. ; Bhavsar, Deepa ; Hunt, Tom ; Stead, Darren ; Ogg, Derek ; Brown, Crystal ; Packer, Martin J. ; Guichard, Sylvie ; Kettle, Jason G. ; Campbell, Andrew ; Stokes, Steve ; Smith, James M. ; Smith, Aaron ; Grondine, Michael ; Jones, Rhys D. O. ; Ye, Yang ; Tucker, Michael

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

100 Deals associated with AZD-3229

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 1	KR	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Advanced cancer	Phase 1	ES	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Advanced cancer	Phase 1	FR	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Advanced cancer	Phase 1	US	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Advanced Malignant Solid Neoplasm	Phase 1	KR	Ningbo Xinwan Pharmaceutical Technology Co., Ltd.	06 Aug 2021
Gastrointestinal Stromal Tumors	Phase 1	KR	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Gastrointestinal Stromal Tumors	Phase 1	FR	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Gastrointestinal Stromal Tumors	Phase 1	ES	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Gastrointestinal Stromal Tumors	Phase 1	US	Ningbo Taikang Pharmaceutical Technology Co. Ltd.	06 Aug 2021
Neoplasms	Phase 1	CN	Ningbo Xinwan Pharmaceutical Technology Co., Ltd.	06 Aug 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04936178 (Phase 1 study of NB003, ASCO2024)	Phase 1	Gastrointestinal Stromal Tumors ctDNA	42	NB003 20mg	(unqqnhihud) = liczfqyibn aidgotpwce (irsmmsuxmr ) View more	Positive	24 May 2024
				NB003 30mg	(unqqnhihud) = awoudocgeo aidgotpwce (irsmmsuxmr ) View more