GDC-0134 - Moligand™ , Inhibitor of mitogen-activated protein kinase kinase kinase 12, CAS No.G610529, Inhibitor of mitogen-activated protein kinase kinase kinase 12

CAS: G610529 Cat. No.: G610529 PubChem CID: 86298636

GRADE & PURITY Moligand™

Synonyms

RG-6000 | SCHEMBL16210454 | 4N6KQ7D685 | 2-Pyridinamine, 3-(difluoromethoxy)-5-(2-(3,3-difluoro-1-pyrrolidinyl)-6-(1S,4S)-2-oxa-5-azabicyclo(2.2.1)hept-5-yl-4-pyrimidinyl)- | GDC0134 | GDC-0134 | GTPL11506 | UNII-4N6KQ7D685 | 1637394-01-4 | compound 279

Storage

Room temperature

Specifications

Sinonimi

RG-6000 | SCHEMBL16210454 | 4N6KQ7D685 | 2-Pyridinamine, 3-(difluoromethoxy)-5-(2-(3,3-difluoro-1-pyrrolidinyl)-6-(1S,4S)-2-oxa-5-azabicyclo(2.2.1)hept-5-yl-4-pyrimidinyl)- | GDC0134 | GDC-0134 | GTPL11506 | UNII-4N6KQ7D685 | 1637394-01-4 | compound 279

Specifiche e purezza

Moligand™

Condizioni di conservazione di stoccaggio

Room temperature

Grado

Moligand™

Tipo di azione

INHIBITOR

Meccanismo d'azione

Inhibitor of mitogen-activated protein kinase kinase kinase 12

Nomi e identificatori

• Sorrisi canonici: FC(Oc1cc(cnc1N)c1cc(nc(n1)N1CCC(C1)(F)F)N1C[C@@H]2C[C@H]1CO2)F
• InChIKey: SKMKJBYBPYBDMN-RYUDHWBXSA-N
• INCHI: 1S/C19H20F4N6O2/c20-17(21)31-14-3-10(6-25-16(14)24)13-5-15(29-7-12-4-11(29)8-30-12)27-18(26-13)28-2-1-19(22,23)9-28/h3,5-6,11-12,17H,1-2,4,7-9H2,(H2,24,25)/t11-,12-/m0/s1
• Isomeri SMILES: C1CN(CC1(F)F)C2=NC(=CC(=N2)N3C[C@@H]4C[C@H]3CO4)C5=CC(=C(N=C5)N)OC(F)F
• PubChem CID: 86298636

Taxonomic Classification

Taxonomy Tree

• Kingdom Organic compounds
  • Superclass Organoheterocyclic compounds
    • Classe Diazines
      • Subclass Pyrimidines and pyrimidine derivatives

• Kingdom: Organic compounds
• Superclass: Organoheterocyclic compounds
• Classe: Diazines
• Subclass: Pyrimidines and pyrimidine derivatives
• Intermediate Tree Nodes: Not available
• Direct Parent: Pyridinylpyrimidines
• Alternative Parents: Dialkylarylamines Aminopyrimidines and derivatives Aminopyridines and derivatives Morpholines Imidolactams Pyrrolidines Oxolanes Heteroaromatic compounds Oxacyclic compounds Dialkyl ethers Azacyclic compounds Primary amines Organofluorides Hydrocarbon derivatives Alkyl fluorides
• Molecular Framework: Aromatic heteropolycyclic compounds
• Substituents: Pyridinylpyrimidine - Dialkylarylamine - Aminopyridine - Aminopyrimidine - Morpholine - Oxazinane - Pyridine - Imidolactam - Pyrrolidine - Heteroaromatic compound - Oxolane - Oxacycle - Azacycle - Dialkyl ether - Ether - Hydrocarbon derivative - Organonitrogen compound - Organofluoride - Organohalogen compound - Alkyl fluoride - Organooxygen compound - Alkyl halide - Organic oxygen compound - Organic nitrogen compound - Primary amine - Amine - Aromatic heteropolycyclic compound
• Descrizione: This compound belongs to the class of organic compounds known as pyridinylpyrimidines. These are compounds containing a pyridinylpyrimidine skeleton, which consists of a pyridine linked (not fused) to a pyrimidine by a bond.
• External Descriptors: Not available

Data sources

1. Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, Fahy E, Steinbeck C, Subramanian S, Bolton E, Greiner R, and Wishart DS. ClassyFire: Automated Chemical Classification With A Comprehensive, Computable Taxonomy. Journal of Cheminformatics, 2016, 8:61.

DOI: 10.1186/s13321-016-0174-y

Obiettivi associati (umani)

MAP3K12 Tchem Mitogen-activated protein kinase kinase kinase 12 (2 Activities)

Discover Target: MAP3K12

Activity Type	Activity Value -log(M)	Mechanism of Action	Activity Reference	Publications (PubMed IDs)

MAP3K13 Tchem Mitogen-activated protein kinase kinase kinase 13 (265 Activities)

Discover Target: MAP3K13

Activity Type	Relation	Activity value	Units	Action Type	Journal	PubMed Id	doi	Assay Aladdin ID

Meccanismi d'azione

Application Protocols

The following are generalized research protocols suitable for small-molecule kinase inhibitors. They are provided as practical guidance and are not item-specific validated methods.

A. Biochemical kinase inhibition (endpoint readout)

• Prepare a 10–50 mM DMSO stock. Perform 10-point half-log serial dilutions in DMSO.
• In assay buffer (e.g., 50 mM HEPES, pH 7.5, 10 mM MgCl2, 0.01% Tween-20), assemble enzyme and substrate at concentrations ensuring initial-rate conditions.
• Add inhibitor dilutions to achieve final DMSO ≤1–2% v/v. Preincubate 10–30 min if needed. Initiate with ATP. Quench after a fixed time and quantify product (e.g., ADP-Glo, radiometric, LC–MS).
• Fit dose–response curves with appropriate models, applying vehicle background subtraction.

B. Cellular assay for pathway modulation

• Dissolve compound in DMSO; prepare working dilutions. Treat cells under necroptosis-inducing conditions as appropriate to your model.
• Maintain identical vehicle controls. Read endpoints (e.g., viability, pathway biomarkers) and confirm on-target effects via genetic/chemical controls.

C. Thermal shift/target engagement (CETSA)

• Incubate cells or lysates with compound; apply temperature gradient; quantify protein stabilization by immunoblot or MS.

Note: Concentrations, incubation times, and detection modalities must be optimized per system. Consult the CoA/Spec Sheet for any handling notes.

Biological Roles

Literature context (not item-specific claims): GDC-0134 is reported as a selective inhibitor of RIPK1 (Receptor-Interacting Protein Kinase 1), a serine/threonine kinase that integrates signals from death receptors (e.g., TNFR1) and pattern-recognition pathways.

• Pathway positioning: RIPK1 acts as a key node determining cell fate among survival (NF-κB activation), apoptosis (via caspase-8), and necroptosis (with RIPK3/MLKL). Its kinase activity is particularly implicated in necroptotic signaling.
• Mechanistic considerations: Small-molecule inhibition of RIPK1’s kinase function is commonly used to dissect TNFα-induced signaling bifurcation, distinguish scaffolding vs catalytic roles, and map checkpoints controlled by ubiquitination and phosphorylation.
• Experimental use: As a pathway probe, RIPK1 inhibitors enable
  • validation of on-pathway engagement (e.g., rescue from necroptotic stimuli in cellular models),
  • delineation of cross-talk with MAPK/JNK and NF-κB cascades,
  • chemoproteomic target engagement profiling.
• Selectivity: Kinase selectivity panels and cellular phenotypic readouts should be employed to confirm on-target effects and rule out off-target liabilities (general recommendation).

No medical or clinical claims are made for this product. It is provided strictly for research use to interrogate signaling biology and cellular mechanisms linked to RIPK1 per user-designed experiments.

Buffer Applications

This product is not a buffering agent and is not typically used to prepare pH buffer systems. For biochemical assays involving kinase inhibition:

• Vehicle: Prepare concentrated DMSO stocks and dilute into an appropriate assay buffer (e.g., HEPES, Tris, or phosphate-based buffers) with Mg2+ where required for kinase activity. Choose buffers with minimal UV background if spectrophotometric reads are used.
• Protein compatibility: Maintain ionic strength and pH optimal for the enzyme system. Include low levels of non-ionic detergents only if needed to reduce aggregation or nonspecific binding, verifying no interference with the readout.

Item-specific buffer-related specifications (pH stability ranges, solubility limits in aqueous media) are not provided for this item; consult the CoA/Spec Sheet and confirm empirically.

Green Alternatives

Because GDC-0134 is a research-use bioactive tool compound rather than a process solvent or stoichiometric reagent, conventional green-chemistry substitution frameworks apply only indirectly. Nonetheless, greener practices can be implemented around its use:

• Solvent minimization: Use high-concentration DMSO stocks to reduce total solvent volumes in screening and biology workflows. Adopt acoustic dispensing to minimize DMSO usage.
• Safer solvents in work-up: If dissolution for analytics allows, prefer ethanol/water or isopropanol/water over chlorinated solvents for sample prep, provided compound solubility and stability are adequate (validate by recovery experiments).
• Energy efficiency: Store at room temperature as indicated (Product Data) to avoid unnecessary cold-chain energy consumption; protect from light/moisture as needed.
• Waste reduction: Consolidate dilute assay waste and segregate halogenated from non-halogenated solvents to facilitate compliant disposal.

Comparison (contextual)

• DMSO vs DMF/NMP: DMSO is generally regarded as a safer polar aprotic solvent with a more favorable hazard profile than DMF/NMP; prefer DMSO when feasible. However, if solubility requires DMF/NMP, minimize concentrations and exposure.

Note: No alternative “green” replacement exists for the active itself; green measures target handling, solvent selection, and waste management.

Pharmaceutical Uses

No pharmacopeial status or excipient role is provided for this item. GDC-0134 is offered for research use only and is not intended for human or veterinary use.

Research/formulation context (general)

• Reference standard: Can serve as a reference/control compound in discovery biology and analytical characterization workflows (e.g., LC–MS retention benchmarking in method development for kinase inhibitors).
• Preformulation studies: If conducting laboratory solubility or stability screens (for research purposes), assess solvent/cosolvent systems (DMSO, ethanol/water, PEG-containing media) and monitor for precipitation on dilution into aqueous buffers.
• Solid form: Where relevant, determine polymorph/amorphous state and hydrate/solvate tendencies, as these can impact dissolution and assay reproducibility.

Regulatory note

• Not produced to GMP and not approved for therapeutic, diagnostic, or clinical use. No claims are made regarding safety or efficacy in humans or animals.

Item-specific pharmacopeial or regulatory listings: Not specified for this item; refer to CoA/Spec Sheet.

Physical Properties

Only limited item-specific physical data are available in the Product Data. Do not infer specifications from general literature; for acceptance criteria, rely on the item’s CoA/Spec Sheet.

Item-specific

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight (spec): Not specified for this item; refer to CoA/Spec Sheet.
• Other specs (mp/bp, density, water, residual solvents, UV cutoff): Not specified for this item; refer to CoA/Spec Sheet.

General/literature context (for planning only; not item specs)

• Small-molecule kinase inhibitors like GDC-0134 are commonly crystalline or amorphous solids with low aqueous solubility and good solubility in polar aprotic organics (e.g., DMSO, DMF) and certain chlorinated solvents. Actual solubility depends on exact structure and salt/form.
• Working stock solutions in DMSO (e.g., 10–50 mM) are commonly prepared for biochemical assays; final assay DMSO is typically kept ≤1–2% v/v to protect enzyme activity (general practice, not item-specific).

Analytical characterization (recommendations)

• Verify identity and purity by LC–MS and HPLC (UV/Vis or MS detection), and confirm dryness by Karl Fischer if hydration impacts assay performance.
• If optical activity is relevant (chiral forms), circular dichroism (CD) or chiral HPLC may be used; confirm need from CoA.

Quality and Grades

• Grade: Moligand™ — Aladdin’s research-use ligand/compound library grade. This designation indicates suitability for discovery biology, target engagement studies, assay development, and screening where verified identity and high assay fitness are needed.

What Moligand™ typically entails (general description; not item-specific specs)

• Identity confirmation by orthogonal methods (e.g., LC–MS; 1H NMR as available).
• High purity suitable for biochemical/biophysical assays; exact purity threshold, residual solvent limits, and counterion/form are defined on the CoA/Spec Sheet.
• Packaging intended to minimize moisture and oxidation exposure, supporting reproducibility in screening assays.

Item-specific notes

• Purity, water content, residual solvents, salt/form, and any stabilizers: Not specified for this item; refer to CoA/Spec Sheet.
• Appearance and batch-specific analytical data: Refer to CoA/Spec Sheet.

Practical guidance

• Upon receipt, record lot/batch number and link all assay results to that batch to ensure traceability.
• For sensitive biochemical assays, perform a quick in-house QC (e.g., HPLC purity check, LC–MS) before large screening runs.
• If orthosteric/ATP-site binders are suspected, consider verifying ATP concentration effects in your assay to confirm on-target behavior.

Reaction and Applications

This product is a bioactive small-molecule tool compound, not a synthetic reagent. As such, classical organic “reagent” applications (e.g., nucleophilic substitutions, reductions) are not typically relevant.

Research applications (general/literature context)

• Target class: Reported in literature as a selective inhibitor of RIPK1, a serine/threonine kinase central to TNF receptor signaling and programmed cell death pathways (general literature note).
• Use cases: Benchmark/control compound in biochemical kinase assays, target engagement studies (e.g., CETSA, NanoBRET), cellular pathway modulation, and mechanism validation experiments in necroptosis/apoptosis studies.
• Profiling: Suitable for kinase panel profiling to assess selectivity versus RIPK family members and broader kinome (run with consistent ATP concentrations and Mg2+ to reflect physiological conditions; general guidance).

Assay practicality

• Prepare concentrated DMSO stocks for accurate serial dilutions across dose–response ranges.
• Include vehicle controls and counter-screens (e.g., off-target kinases, unrelated enzymes) to identify assay artifacts.
• Monitor for aggregation-based inhibition (test with low non-ionic detergent and/or dynamic light scattering where feasible).

Note: Exact potency, selectivity values, and assay-optimized solvent/vehicle limits are not specified for this item; consult primary literature and confirm empirically in your system.

Reaction Conditions

Classical synthetic reaction conditions are not applicable because this product is used as a bioactive tool rather than a reagent. For experimental biology and biochemistry, the relevant “conditions” relate to assay setup.

General assay condition guidance (literature/practice; not item-specific)

• Stock solutions: Prepare in dry DMSO, filter if necessary (0.22 µm PTFE) to remove particulates.
• Assay buffers: Choose kinase-compatible buffers (e.g., HEPES or Tris), include Mg2+ and ATP at concentrations appropriate to the assay design; maintain consistent DMSO across control and treated wells.
• Temperature and timing: Conduct biochemical assays at 25–37°C; allow preincubation of inhibitor with enzyme (e.g., 10–30 min) if time-dependent inhibition is suspected.
• Readouts: Use ADP-coupled, radiometric, TR-FRET, or mobility-shift assays; validate linearity with respect to enzyme concentration and time.
• Controls: Include no-enzyme, no-substrate, and vehicle controls; consider a known RIPK1 comparator where available.

No item-specific potency, kinetic parameters, or stability in particular buffers are provided; determine empirically under your assay conditions.

Safety and Handling

Authoritative safety information is provided in the product’s SDS. The following guidance is general and conservative for research-use small molecules.

Item-specific hazard data

• GHS classification: Not specified for this item; refer to SDS.
• Pictograms / Signal word / H-statements: Not specified for this item; refer to SDS.

General laboratory precautions

• Handle in a chemical fume hood; avoid inhalation of dust/aerosols and skin/eye contact.
• PPE: lab coat, safety glasses, and appropriate chemical-resistant gloves (e.g., nitrile). Change gloves regularly.
• Avoid generating dust; use antistatic precautions when weighing fine powders.

Incompatibilities and stability considerations

• Avoid strong oxidizing agents and strong acids/bases unless compatible with the specific structure; segregate from reactive chemicals.
• Protect from prolonged light and moisture until form-specific stability is confirmed. Use desiccation if hygroscopicity is suspected.

First aid (overview; consult SDS)

• Skin/eye contact: Rinse with water for at least 15 minutes; remove contaminated clothing; seek medical attention as needed.
• Inhalation: Move to fresh air; seek medical attention if symptoms occur.
• Ingestion: Rinse mouth; do not induce vomiting; seek medical attention.

Waste disposal

• Collect as organic chemical waste. Follow institutional and local regulations.

Solvent Selection

Item-specific solubility data are not provided. The following are general recommendations for small, hydrophobic kinase inhibitors used as research tools.

Primary choices

• DMSO: Typically the first choice for stock solutions owing to broad solvating power and enzyme-compatibility at low final percentages. Typical working stocks: 10–50 mM (general practice).
• DMF or NMP: Useful alternatives when DMSO solubility is insufficient; verify enzyme tolerance and include proper vehicle controls.

Aqueous compatibility

• Aqueous solubility is often limited. To prepare assay plates, dilute DMSO stocks into assay buffer to a final DMSO of ≤1–2% v/v (general practice). Utilize gentle vortexing and brief sonication to avoid precipitation.

Co-solvent strategies

• If precipitation appears on dilution: increase DMSO carryover slightly within assay tolerance, or include non-ionic surfactants at low concentrations when biocompatible (e.g., 0.01–0.05% Tween-20), validating no assay interference.

Comparison (general)

• DMSO vs ethanol: DMSO generally offers higher solubility and better enzyme stability; ethanol may be acceptable at ≤1% but can perturb some proteins.
• DMSO vs DMF/NMP: DMF and NMP can increase solubility but may be less tolerated by some enzymes/cells; always run vehicle controls.

Note: For method validation, consult the item’s CoA/Spec Sheet for any provided solvent/solubility guidance.

Storage and Reconstitution

Storage

• Storage condition (Product Data): Room temperature.
• Protect from moisture and light until usage is characterized. Keep container tightly closed. If long-term storage is planned, consider desiccation and inert-atmosphere storage as prudent practice for small molecules.

Reconstitution

• Solvent: Item-specific solubility is not provided. For small-molecule kinase inhibitors, DMSO is typically suitable for preparing concentrated stock solutions. Verify solubility and stability empirically.
• Concentration: Choose a stock concentration that enables low final DMSO in assays (often 10–50 mM in DMSO; general practice). Ensure complete dissolution by gentle warming (≤40°C) and brief sonication if needed.
• Filtration: If particulate matter is observed, sterile-filter through 0.22 µm PTFE for cell-based work.

Handling

• Avoid repeated freeze–thaw of stock solutions. Aliquot DMSO stocks into single-use vials; store according to your internal stability assessment (commonly −20°C for DMSO stocks as a general practice, if compatible).
• Record preparation date, solvent, and concentration on each aliquot.

Specifications not provided

• Appearance, exact solubility limits, hygroscopicity, and stability profile: Not specified for this item; refer to CoA/Spec Sheet and validate under your lab conditions.

Research use only.

Structure and Identity

GDC-0134 is supplied as a research-use small-molecule tool compound in Aladdin’s Moligand™ collection. Public literature associates GDC-0134 with RIPK1 kinase inhibition; however, detailed structural parameters for this specific catalog item are not provided below and should be confirmed against the CoA/Spec Sheet.

• SKU: G610529
• Product name: GDC-0134 (research-use only)
• CAS: G610529 (catalog identifier as provided; not a CAS RN)
• PubChem CID: 86298636 (literature identifier)
• InChIKey: 338341 (as provided in Product Data)
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.

Structural description

• Item-specific structural features: Not specified for this item; refer to CoA/Spec Sheet.
• Literature/context: GDC-0134 is reported in the literature as a small-molecule inhibitor targeting RIPK1 (Receptor-Interacting Protein Kinase 1). Structural disclosure and exact stereochemistry should be verified via the cited PubChem CID or primary literature (general literature note).

Note on identity confirmation

• Recommended orthogonal checks for this item include LC–MS and 1H NMR comparison to a reference spectrum, and HPLC purity assessment, using the CoA/Spec Sheet as the authoritative source for acceptance criteria.

Synthetic Utility

This product is a finished small-molecule tool compound and is not typically employed as a synthetic building block or reagent.

• Use focus: Biological and biochemical experimentation (e.g., kinase inhibition studies, target engagement assays) rather than participation in chemical transformations.
• Derivatization: If analog generation is desired for SAR exploration, synthetic strategies would be designed de novo from published core scaffolds of RIPK1 inhibitors (literature-dependent) rather than direct functionalization of the final molecule, which may be structurally complex and sensitive.
• Analytical chemistry: While not a reagent, it can aid in validating analytical methods (e.g., LC–MS method development, stability-indicating methods) for related chemotypes.

Item-specific functional group reactivity and protecting-group compatibility are not provided. For chemists considering semi-synthesis or probe conjugation, consult the primary literature and the CoA for structural confirmation before planning any transformations.

Target Specificity

Item-specific target specificity data are not provided in the Product Data. Literature context indicates GDC-0134 has been reported as a selective inhibitor of RIPK1 kinase.

• Primary target (literature): RIPK1 (Receptor-Interacting Protein Kinase 1). No numeric affinity/IC50 values are provided here.
• Selectivity considerations: Confirm selectivity by kinome profiling and orthogonal cellular readouts (e.g., protection from necroptotic stimuli without undesired effects on unrelated kinases). Include ATP-competition studies to assess binding mode if relevant.
• Off-target assessment: Implement broad counter-screens and cytotoxicity baselines to rule out nonspecific effects at higher concentrations.

For definitive, lot-specific information on target binding and any additional annotated targets, refer to the CoA/Spec Sheet or user-generated validation data. No claims are made beyond research use.