WZH-17-002 | ALK PROTAC Degrader

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WZH-17-002 | ALK PROTAC Degrader

Original price was: $38.00.Current price is: $29.00.

WZH-17-002 is an ALK PROTAC degrader derived from WZH-15-125. It achieves a DC50 of 25 nM, showing superior activity against Lorlatinib-resistant ALK mutations. In preclinical xenograft models, WZH-17-002 significantly reduces drug resistance and tumor burden, offering a next-generation approach to studying ALK-driven NSCLC and targeted protein degradation.

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Description

Product Description

Introduction

WZH-17-002 represents a next-generation strategy for overcoming ALK inhibitor resistance through targeted protein degradation (PROTAC technology). Unlike conventional small-molecule inhibitors that simply block kinase activity, WZH-17-002 is designed to induce proteasomal degradation of the ALK fusion protein, leading to sustained suppression of oncogenic signaling.

The compound is based on WZH-15-125 (a highly potent ALK inhibitor effective against Lorlatinib-resistant mutations) but is extended with a linker and E3 ligase ligand to form a PROTAC. This design allows WZH-17-002 not only to inhibit but also to eliminate mutant ALK proteins, thereby reducing the likelihood of adaptive resistance.

Research Significance

  1. Targeted Degradation vs. Inhibition
    Traditional ALK inhibitors such as crizotinib, ceritinib, alectinib, brigatinib, and Lorlatinib eventually encounter resistance mutations like G1202R and compound G1202R/L1196M. WZH-17-002 degrades the ALK protein entirely, providing a stronger and more durable suppression compared to mere inhibition.

  2. Potency in Resistant Mutations

    • DC50 = 25 nM indicates potent degradation capacity.

    • Specifically designed to tackle Lorlatinib-resistant ALK compound mutations.

    • Demonstrated efficacy in EML4-ALK G1202R/L1196M xenograft mice, a gold-standard preclinical resistance model.

  3. PROTAC Design Components

    • Pink segment (ALK ligand): Derived from WZH-15-125 (HY-174314), provides high affinity for ALK kinase.

    • Blue segment (CRBN ligase ligand): HY-14658, a cereblon ligand, recruits the E3 ubiquitin ligase.

    • Black segment (linker): HY-174316, flexible linker optimized for proximity-induced ubiquitination.

  4. Preclinical Validation
    WZH-17-002 has been shown to:

    • Reduce tumor growth in NSCLC xenografts.

    • Overcome Lorlatinib resistance in compound mutant models.

    • Provide a novel proof-of-concept for ALK degradation therapy.

Research Applications

  • NSCLC resistance studies with EML4-ALK fusions.

  • Comparison between inhibition (WZH-15-125) and degradation (WZH-17-002).

  • Drug discovery for PROTAC-based therapies.

  • Mechanistic exploration of protein degradation pathways.

  • Xenograft modeling of compound ALK resistance.


Product Specifications

ParameterDetails
Product NameWZH-17-002
OriginWZH-15-125-based PROTAC degrader
Target ProteinAnaplastic lymphoma kinase (ALK)
DC5025 nM
Key ActivityALK degradation in resistant models
Resistance CoverageEffective against Lorlatinib-resistant compound mutations (e.g., G1202R/L1196M)
Preclinical ModelInhibits tumor growth in EML4-ALK xenografts
Structural ComponentsALK ligand (HY-174314), CRBN ligand (HY-14658), linker (HY-174316)
Research UsePROTAC development, resistance studies, NSCLC models
Related CompoundsWZH-15-125, Lorlatinib
AppearanceWhite to off-white powder
Purity≥98% (HPLC)
SolubilityDMSO, ethanol
Storage Conditions-20°C, dry, light-protected
Shelf Life≥2 years with proper storage
QC ValidationHPLC, NMR, MS characterization

Mechanism of Action

1. PROTAC Technology

WZH-17-002 follows the PROTAC (Proteolysis Targeting Chimera) paradigm:

  • The ALK ligand binds mutant ALK.

  • The CRBN ligand recruits cereblon E3 ubiquitin ligase.

  • The linker brings both proteins into proximity.

  • ALK is ubiquitinated and degraded via the 26S proteasome.

This mechanism eliminates the target protein, offering a fundamentally different strategy from inhibition.

2. Overcoming Lorlatinib Resistance

  • G1202R mutation disrupts Lorlatinib binding.

  • L1196M gatekeeper mutation adds steric hindrance.

  • Combined G1202R/L1196M compound mutations are essentially untreatable with inhibitors.

  • WZH-17-002 bypasses binding dependency, instead degrading ALK altogether.

3. Preclinical Validation

  • In xenograft models, WZH-17-002 significantly inhibited tumor growth.

  • Reduction of ALK protein expression was confirmed in tumor tissues.

  • Sustained suppression suggests lower probability of secondary resistance.

4. Broader Implications

WZH-17-002 exemplifies how PROTACs can expand druggable space, tackling mutations that render inhibitors ineffective. It also provides a model scaffold for other kinase-targeted degraders.

zh-17-002-Peptide-Manufacturer-Wholesaler


Side Effects

As a research compound, WZH-17-002’s toxicity profile is extrapolated from:

  • On-target degradation risks: Excessive ALK removal may affect normal neuronal development and immune regulation.

  • CNS effects: ALK plays roles in brain development; off-target degradation may alter cognitive/behavioral outcomes.

  • Metabolic changes: Possible lipid/glucose dysregulation.

  • Hepatotoxicity: As with many PROTACs, liver enzyme elevation is a potential concern.

  • Immunological concerns: CRBN-based ligands may affect immune signaling pathways.

Handling Precautions

  • Research use only.

  • Not approved for human or animal therapeutic use.

  • Use PPE and BSL-2 handling conditions.


Disclaimer

WZH-17-002 is intended for laboratory research only. It is not approved for clinical or veterinary use.


Keywords

WZH-17-002, ALK PROTAC degrader, WZH-15-125-based PROTAC, ALK G1202R/L1196M degradation, Lorlatinib resistance, NSCLC xenograft, targeted protein degradation, PROTAC technology, CAS WZH-17-002.


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Additional information

Weight0.8 kg
Dimensions56 × 38 × 56 cm

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1. What is WZH-17-002?

It is a WZH-15-125-based ALK PROTAC degrader with DC50 = 25 nM.

2. What is its main application?

Studying ALK degradation and resistance overcoming in NSCLC research.

3. How does it differ from WZH-15-125?

WZH-15-125 is an inhibitor, while WZH-17-002 is a degrader that removes ALK proteins.

4. What mutations does it cover?

Effective against Lorlatinib-resistant ALK compound mutations, including G1202R/L1196M.

5. Has it been tested in vivo?

Yes, it significantly inhibited tumor growth in EML4-ALK xenograft models.

6. What is the degradation potency?

DC50 = 25 nM.

7. Can it be used in PROTAC research?

Yes, it is an excellent tool for validating ALK-targeted PROTAC strategies.

8. What are its components?
  • ALK ligand (HY-174314)

  • CRBN ligand (HY-14658)

  • Linker (HY-174316)

9. How should it be stored?

At -20°C, dry, and protected from light.

10. Is it approved for therapeutic use?

No, it is for research use only.

11. Can it cross the blood-brain barrier?

Like Lorlatinib and its derivatives, it is designed with CNS penetration potential.

12. What payment methods are supported?

T/T, PayPal, and cryptocurrency.


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