PI3Kα/HDAC6-IN-1 , CAS No.3007565-26-3

CAS: 3007565-26-3 Cat. No.: P1426686 Fórmula: C₂₇H₃₀F₃N₇O₆S₂ Peso molecular: 669.70

Storage

Store at -20°C

Shipped In

Ice chest + Ice pads

Visão geral

PI3Kα/HDAC6-IN-1 (compound 21j) is a dual PI3Kα/HDAC6 inhibitor with IC 50 of 2.9 and 26 nM, respectively. PI3Kα/HDAC6-IN-1 also inhibits AKT (Ser473) phosphorylation and induces the accumulation of acetylated α-tubulin without affecting acetylated histones H3 and H4. PI3Kα/HDAC6-IN-1 efficiently inhibits L-363 cell line ( IC 50 =0.17 μM) and has good anti-cancer activity.

Specifications

Condições de armazenamento de armazenamento

Store at -20°C

Enviado em

Ice chest + Ice pads

Este produto requer transporte de cadeia fria. Serviços terrestres e outros serviços econômicos não estão disponíveis.

Tipo de ação

INHIBITOR

Nomes e identificadores

Peso molecular

669.70

Application Protocols

No item-specific, validated protocols are provided in the Product Data. The following are general starting points to be adapted and optimized per lab SOPs.

• Biochemical enzyme assay (general):

  • Prepare a 10–50 mM DMSO stock (as solubility permits). Serially dilute in DMSO to generate a 10-point curve (e.g., 1:3 dilutions).
  • Add to assay mix to achieve a final vehicle concentration ≤1% v/v.
  • Incubate with enzyme/substrate under recommended conditions; quantify activity (fluorogenic substrate for HDAC6; lipid kinase readout for PI3Kα).
  • Fit concentration–response to obtain IC50; verify absence of aggregation (detergent controls, light scattering).

• Cell-based assay (general):

  • Treat cells with a dilution series (typical 0.01–10 µM range to bracket unknown potency) keeping vehicle constant.
  • After incubation (e.g., 1–24 h depending on endpoint), assess biomarkers: p-AKT (S473/T308) for PI3Kα axis; acetyl-α-tubulin for HDAC6.
  • Evaluate cytotoxicity in parallel (e.g., CellTiter assays) to ensure on-target interpretation.

• Data QC: Include positive control inhibitors for each target and inactive analogs/vehicle controls. Replicate across ≥3 biological repeats.

Biological Roles

This section summarizes target biology for context. No medical or clinical claims are made.

• PI3Kα (phosphoinositide 3-kinase alpha): Catalytic subunit p110α with regulatory partners (p85). Catalyzes phosphorylation of PIP2 to PIP3, recruiting PH-domain proteins (e.g., AKT) and propagating survival/growth signaling. Activity is modulated by RTKs and RAS. Key readouts include PIP3 levels, AKT/PRAS40 phosphorylation, and downstream mTORC1 effectors (S6K, 4E-BP1).
• HDAC6 (histone deacetylase 6): A cytoplasmic, Zn2+-dependent deacetylase with two catalytic domains and a ubiquitin-binding zinc finger. Deacetylates non-histone substrates including α-tubulin, HSP90, and cortactin, impacting aggresome formation, protein quality control, and cell motility. Pharmacodynamic marker: acetyl-α-tubulin accumulation upon inhibition.

Implications for research use (general):

• Dual modulation of lipid kinase signaling and cytoplasmic deacetylation enables interrogation of crosstalk between growth-factor pathways and proteostasis/cytoskeletal dynamics.
• Enable mechanistic studies of pathway redundancy, feedback, and adaptive resistance in cell systems.
• Support chemical biology experiments mapping phenotype-to-target relationships via genetic rescue, CRISPR knockouts, or degrader co-treatment.

Recommended controls:

• Orthogonal single-target tool compounds (PI3Kα-selective and HDAC6-selective), inactive analogs, and pathway biomarkers to strengthen causal links.

Buffer Applications

This product is not a buffering agent. Guidance below addresses using buffers to deliver the compound in assays.

• Biochemical PI3K assays: Use validated buffers containing appropriate salts, Mg2+, ATP, and lipid substrates (PIP2 with detergent or vesicles). Maintain low DMSO (≤1% v/v typical) to preserve enzyme activity.
• HDAC6 deacetylase assays: Tris/HEPES buffers (pH ~7.5–8.0, literature) with Zn2+ present; avoid strong metal chelators (EDTA) unless the assay format requires quench.
• Cell-based assays: Deliver from DMSO stocks into culture media; pre-mix with serum-containing media to reduce precipitation. Maintain constant vehicle % across wells.

Practical notes (general):

• Pre-clear buffer solutions by 0.22 µm filtration to reduce background.
• Validate compound stability in your chosen buffer over the full assay time-course.
• For light-sensitive analytes (unknown for this item), use amberware and minimize exposure.

Green Alternatives

Although this item is not a solvent or reagent used in scale synthesis, greener practices can be applied to solution preparation and assay workflows.

Opportunities (general guidance):

• Minimize DMSO volume in final assay to ≤0.1–0.5% v/v where feasible to reduce solvent burden.
• Use aqueous vehicles enhanced with cyclodextrins or lipid carriers to lower reliance on high-toxicity solvents; validate for target compatibility.
• Right-size batch prep: Make only the amount of stock needed to limit chemical waste and reduce the number of freeze–thaw cycles.
• Microscale assays: Adopt miniaturized plates (384/1536-well) to reduce compound and solvent consumption.

Illustrative comparison (general; not item-specific):

• DMSO: excellent solubilizer; high boiling point; environmental persistence—use sparingly and collect as hazardous waste.
• Ethanol: renewable feedstock potential; more benign profile but may inadequately solubilize highly lipophilic inhibitors.
• Aqueous + cyclodextrin: greener matrix; may introduce assay interference—requires careful controls.

Implementation tips:

• Validate solubility and activity in greener vehicles early in method development.
• Employ sealed plates or low-evaporation lids to prevent solvent loss and concentration drift.
• Coordinate with EHS for waste segregation and solvent recycling where available.

Pharmaceutical Uses

For research use only. No medical or clinical uses are claimed or supported.

Relevant non-clinical/lab contexts (general guidance):

• Reference control in screening cascades or target validation studies focusing on PI3Kα and HDAC6 pathways.
• Analytical standard for method development in LC–MS bioanalytical workflows (retention behavior, ionization conditions) after confirming identity and purity.
• Formulation research: Exploratory solubilization strategies (co-solvents, surfactants, cyclodextrins) to understand delivery variables in preclinical assay systems. Any such work should remain strictly non-clinical and for in vitro/in vivo research under institutional approvals.

Documentation:

• Maintain complete records of lot numbers, purity data, and storage conditions to ensure data integrity and reproducibility in regulated lab environments.

Physical Properties

Item-specific physicochemical constants have not been provided.

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Melting point (mp): Not specified for this item; refer to CoA/Spec Sheet.
• Boiling point (bp): Not applicable/unknown for a non-volatile small molecule; specific value not provided.
• Density/refractive index: Not specified for this item; refer to CoA/Spec Sheet.
• Solubility (item-specific): Not specified for this item; refer to CoA/Spec Sheet.

General literature guidance for PI3K/HDAC inhibitor-like small molecules (not item-specific):

• Often sparingly soluble in water at neutral pH; typically solubilized as DMSO stock solutions for biochemical and cell-based assays.
• May exhibit improved apparent solubility in aqueous buffers with co-solvents (e.g., 0.1–1% DMSO) or with additive systems (cyclodextrin, serum proteins), subject to assay compatibility.
• Many kinase/HDAC ligands display moderate-to-high lipophilicity and multiple heteroatoms (H-bond donors/acceptors) that drive target binding; actual logP/logD and pKa values must be confirmed from the CoA or vendor technical note.

Practical notes:

• Establish a solubility curve empirically in your assay media (DMSO, PBS, cell culture media) to avoid precipitation.
• Filter (0.22 µm) or centrifuge stocks before sensitive assays (SPR, BLI, HTRF) to remove particulates.
• Record solution stability over time and temperature; perform re-analysis (HPLC/LC–MS) if solutions are stored >24–48 h.

Quality and Grades

• Grade/Purity (item-specific): Not specified for this item; refer to CoA/Spec Sheet.

Interpretation and typical expectations for screening compounds (general guidance; not item-specific):

• Screening-library small molecules are commonly supplied at ≥95% HPLC area purity, confirmed by LC–MS and sometimes 1H NMR. However, do not assume—verify the stated purity and analytical methods in the CoA.
• If UV transparency is relevant (e.g., enzyme kinetics by UV–vis), request a spectral profile. For fluorescence assays, ask about intrinsic fluorescence/quencher behavior.
• For SAR and orthogonal validation, ensure batch-to-batch consistency with identity confirmation (HRMS/NMR) and purity profile (HPLC/UPLC with PDA and MS detectors).
• If chiral: request enantiomeric ratio or absolute configuration information. If salt form: confirm counterion content and residual inorganic salts.

Practical recommendations:

• Implement incoming QC suitable for your workflow (UPLC purity check, MS identity, and optional NMR).
• Establish internal acceptance criteria (e.g., purity threshold, residual solvent limits) aligned to your assay sensitivity.
• Retain a certificate copy linked to lab notebook entries for data integrity and regulatory reviews.

Reaction and Applications

Intended use is as a dual-target small-molecule research probe, not as a synthetic reagent. The following covers research applications in chemical biology and screening.

Research applications (general; expand per your assay design):

• Target engagement studies: Assess interaction with PI3Kα and HDAC6 using biochemical enzymatic assays (ATP turnover, PIP3 formation assays for PI3Kα; deacetylation assays for HDAC6).
• Cell-based pathway modulation: Monitor downstream readouts (e.g., AKT phosphorylation for PI3Kα axis; α-tubulin acetylation for HDAC6) as pharmacodynamic markers. Include appropriate positive/negative controls.
• Selectivity profiling: Broader kinase and HDAC panels to characterize off-targets and build MoA confidence; counterscreens for cytotoxicity and PAINS liabilities.
• Chemical probe validation: Time-course, washout, and concentration–response experiments to establish potency and reversibility in your system.
• Combination studies: Evaluate synergy/antagonism with orthogonal agents (e.g., PI3K pathway or tubulin-modulating tool compounds) while tracking confounders like DMSO content.

Good practices:

• Verify enzyme integrity (fresh cofactors, correct lipid substrates for PI3K assays). For HDAC6, account for Zn2+ dependence and avoid metal-chelating buffers unless specified.
• Implement orthogonal readouts (WB, ELISA, high-content imaging) to mitigate assay artifacts.
• Document compound handling (lot, stock concentration, freeze–thaw cycles) to ensure data reproducibility.

Reaction Conditions

Not typically applicable. This item is used as a biological probe, not as a reagent or catalyst in synthetic transformations.

If performing derivatization or conjugation for exploratory SAR (general guidance only):

• Choose anhydrous, oxygen-free conditions when handling sensitive heteroaromatics.
• Common solvent choices include DMF, DMSO, or acetonitrile; add base or coupling agents as dictated by the functional groups being modified (e.g., amide coupling reagents).
• Monitor reactions by LC–MS and UPLC; purify by preparative HPLC if necessary.

These notes are generic and should not be interpreted as specifications for this item.

Safety and Handling

Authoritative safety information must be taken from the SDS. The following summarizes general best practices for small-molecule research probes.

• GHS classification / pictograms / H-statements / signal word: Not specified for this item; refer to SDS.
• Primary hazards (general): Many kinase/HDAC ligands may cause irritation to skin, eyes, and respiratory tract; systemic toxicity is unknown. Avoid inhalation of powders and contact with skin/eyes.
• Personal protective equipment (PPE): Lab coat, safety glasses, and appropriate chemically resistant gloves (e.g., nitrile). Use a certified fume hood for weighing and solution prep.
• Handling: Minimize dust formation. Use antistatic tools for powders. Prepare solutions with clean, dry syringes or volumetrics. Label DMSO stocks with concentration and date.
• Incompatibilities (general): Strong oxidizers and strong acids/bases may cause degradation; avoid prolonged exposure to moisture, light, and elevated temperature.
• Spill/Exposure response:
  • Skin/eye contact: Rinse with water for ≥15 min; remove contaminated clothing; seek medical attention as per SDS.
  • Inhalation: Move to fresh air; obtain medical attention if symptoms persist.
  • Ingestion: Rinse mouth; do not induce vomiting; seek medical advice.
• Waste: Dispose of solutions and contaminated materials as organic chemical waste in accordance with institutional and local regulations.
• Always defer to the product-specific SDS and institutional EHS guidance.

Solvent Selection

This product is a small-molecule inhibitor intended for biochemical/cell assays rather than as a bulk solvent. Solvent selection here refers to preparation of stock and working solutions.

General solvent guidance (not item-specific):

• DMSO: Widely used vehicle; miscible with water and most organics; suitable for high-concentration stocks. Verify assay tolerance (commonly 0.1–1% v/v in final well).
• DMF/NMP: Stronger solvents for difficult-to-dissolve analytes; consider cytotoxicity and leachables; use sparingly.
• Aqueous buffers (PBS, HEPES) with co-solvent: For working dilutions; add DMSO stocks into vigorously mixed buffer to avoid precipitation.
• Additives: Cyclodextrins or serum proteins can enhance apparent solubility; confirm no target interference.

Comparison (general characteristics):

• DMSO: polar aprotic, high dielectric, water-miscible, broad solubilizing power.
• Ethanol: protic, water-miscible, may affect membrane permeability and enzyme activity at >1–2%.
• PEG-400: low volatility, increases viscosity; may slow diffusion kinetics in assays.

Practical tips:

• Prepare concentrated DMSO stocks (e.g., 10–50 mM as assay permits), then serially dilute into buffer.
• Pre-warm or sonicate briefly to aid dissolution; avoid prolonged heating.
• Confirm absence of precipitation by visual check or light scattering in the actual assay matrix.

Storage and Reconstitution

• Storage conditions (item-specific): Store at -20°C.
• Shipping (item-specific): Shipped in ice chest with ice pads.

General handling and reconstitution guidance (not item-specific):

• Allow vial to equilibrate to room temperature in a desiccator before opening to prevent moisture condensation.
• For initial use, prepare a concentrated stock in an anhydrous solvent such as DMSO. Vortex/sonicate briefly to fully dissolve. Filter if needed (0.22 µm PTFE for organic solutions).
• Aliquot stocks into single-use portions (e.g., 10–50 µL) to avoid repeated freeze–thaw cycles.
• Store aliquots at -20°C (or below) in tightly sealed, chemically compatible containers. Protect from light if the compound is light-sensitive (not specified for this item; verify experimentally).
• Thaw on ice or at room temperature just before use. Avoid prolonged exposure to ambient humidity.
• Record lot number, preparation date, solvent, and concentration on each aliquot.

Stability notes:

• Item-specific stability, hygroscopicity, and light sensitivity are not specified; consult CoA/Spec Sheet and perform confirmatory HPLC/LC–MS checks after extended storage or if activity drifts.

Structure and Identity

Overview: PI3Kα/HDAC6-IN-1 is supplied as a dual-target small-molecule research probe intended for biochemical and cellular studies involving PI3K alpha (p110α) and HDAC6 pathways.

• SKU: P1426686
• Product name: PI3Kα/HDAC6-IN-1
• CAS: 3007565-26-3
• Category: Small molecule library compound (research use)
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.
• InChIKey: Not specified for this item; refer to CoA/Spec Sheet.

Structural features (general guidance):

• As a dual PI3K/HDAC6 inhibitor class, such molecules commonly feature heteroaromatic scaffolds, H-bond donor/acceptor motifs, and lipophilic regions enabling engagement of Class I PI3K ATP sites and the HDAC6 catalytic pocket (zinc-binding region). The exact ring systems, stereochemistry, and functional groups for this CAS are not specified in the provided data.

Identification notes:

• Use the CAS number for unambiguous database cross-referencing.
• Confirm identity by orthogonal methods (e.g., HRMS, 1H/13C NMR, HPLC retention) against the CoA/SDS for this catalog item.
• If your application is SAR-sensitive, request full structural identifiers (SMILES/InChI) prior to assay deployment.

Synthetic Utility

This product is a finished small-molecule tool compound and is not primarily intended as a synthetic building block.

General chemistry perspective (not item-specific):

• Dual-target inhibitors often contain heteroaromatic cores and multiple functional groups that could, in principle, serve as handles for late-stage diversification (e.g., halogen for cross-coupling, amide for derivatization), but such modifications would constitute new analog synthesis rather than routine use of this item as a reagent.
• If analog generation is desired, consider de novo synthesis based on literature scaffolds for PI3K and HDAC6 pharmacophores or leverage parallel synthesis/medchem platforms.

Recommendations:

• Reserve this material for biological evaluation and benchmarking; use separate synthetic routes if structural variants are needed for SAR.

Target Specificity

Item-specific potency and selectivity data are not provided in the Product Data.

• Primary targets (name-level): PI3Kα and HDAC6 (per product name classification).
• Quantitative metrics (IC50/Ki/Kd, panels, off-targets): Not specified for this item; refer to CoA/Spec Sheet and primary literature for this CAS.

Recommendations:

• Perform in-house potency confirmation in your assay format (biochemical and/or cellular) to establish operational IC50 values.
• Profile against selectivity panels (kinases, HDAC isoforms) to identify off-target liabilities and to contextualize phenotypic outcomes.
• Include orthogonal assays (e.g., CETSA/thermal shift, NanoBRET) for cellular target engagement measurements.