SHP2-D26 is the first highly efficient SHP2 degrader. SHP2-D26 needs to bind to VHL-1 and SHP2 proteins when inducing SHP2 degradation, and is ubiquitination-like modification-dependent and proteasome-dependent.

Physicochemical Properties

Molecular Formula	C56H79CLN12O6S2
Molecular Weight	1115.88626885414
Exact Mass	1114.537
CAS #	2458219-65-1
PubChem CID	155930583
Appearance	Off-white to light yellow solid powder
LogP	6.2
Hydrogen Bond Donor Count	6
Hydrogen Bond Acceptor Count	15
Rotatable Bond Count	23
Heavy Atom Count	77
Complexity	1920
Defined Atom Stereocenter Count	4
SMILES	C(N1C[C@H](O)C[C@H]1C(=O)N[C@H](C1C=CC(C2=C(N=CS2)C)=CC=1)C)(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCN1CCN(C(=O)CCC(=O)NC2C=CC=C(SC3=NC=C(N4CCC(N)(C)CC4)N=C3N)C=2Cl)CC1
InChi Key	XJSPAQRZSJUBLB-WQFCSRJTSA-N
InChi Code	InChI=1S/C56H79ClN12O6S2/c1-36(38-17-19-39(20-18-38)49-37(2)61-35-76-49)62-52(74)42-32-40(70)34-69(42)54(75)50(55(3,4)5)65-45(71)16-11-9-7-8-10-12-25-66-28-30-68(31-29-66)47(73)22-21-46(72)63-41-14-13-15-43(48(41)57)77-53-51(58)64-44(33-60-53)67-26-23-56(6,59)24-27-67/h13-15,17-20,33,35-36,40,42,50,70H,7-12,16,21-32,34,59H2,1-6H3,(H2,58,64)(H,62,74)(H,63,72)(H,65,71)/t36-,40+,42-,50+/m0/s1
Chemical Name	(2S,4R)-1-[(2S)-2-[9-[4-[4-[3-[3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl]sulfanyl-2-chloroanilino]-4-oxobutanoyl]piperazin-1-yl]nonanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	SHP2-D26 (0, 3, 10, 30, 100, and 300 nM; 12 hours) efficiently and dose-dependently decreased SHP2 protein in KYSE520 and MV-4-11 cells, with DC50 values of 2.6 nM and 6.0 nM, respectively [1]. In KYSE520 and MV-4-11 cells, SHP2-D26 (100 nM; 0, 2, 4, 8, 12, 24 hours) decreases SHP2 protein levels in 4 hours and finishes SHP2 depletion in 8 hours [1]. For KYSE520 and MV-4-11 cells, the IC50 values of SHP2-D26 (0-100 μM and 0-10 nM, respectively; 4 days) are 0.66 μM and 0.99 nM, respectively[1].
Cell Assay	Cell proliferation assay[1] Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 0-100 μM for KYSE520 cells; 0-10 nM for MV-4-11 cells Incubation Duration: 4 days Experimental Results: KYSE520 and MV-4 The IC50 values in -11 cells were 0.66 μM and 0.99 nM respectively. Western Blot Analysis[1] Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 0, 3, 10, 30, 100, 300 nM Incubation Duration: 12 hrs (hours) Experimental Results: SHP2 protein diminished in a dose-dependent manner with DC50 values of 6.0 and 2.6 nM in KYSE520 and MV-4-11 cells, respectively. Western Blot Analysis[1] Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 100 nM Incubation Duration: 0, 2, 4, 8, 12, 24 hrs (hours) Experimental Results: diminished SHP2 protein levels and completed SHP2 removal within 4 hrs (hours)8 Hour.
References	[1]. Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein [published correction appears in J Med Chem. 2021 Jan 14;64(1):906-908]. J Med Chem. 2020;63(14):7510-7528.

Solubility Data

Solubility (In Vitro)

DMSO : ~83.33 mg/mL (~74.68 mM)

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	0.8961 mL	4.4807 mL	8.9615 mL
	5 mM	0.1792 mL	0.8961 mL	1.7923 mL
	10 mM	0.0896 mL	0.4481 mL	0.8961 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.