CN112480081A - Difunctional molecular compound for inducing SHP2 protein degradation based on Cereblan ligand - Google Patents
Difunctional molecular compound for inducing SHP2 protein degradation based on Cereblan ligand Download PDFInfo
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- CN112480081A CN112480081A CN202011430267.6A CN202011430267A CN112480081A CN 112480081 A CN112480081 A CN 112480081A CN 202011430267 A CN202011430267 A CN 202011430267A CN 112480081 A CN112480081 A CN 112480081A
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Abstract
The invention relates to a bifunctional molecular compound for inducing SHP2 protein degradation based on a Cereblan ligand, belonging to the technical field of medicinal chemistry and biology. The compound can be used for preparing a medicament for treating SHP2 mediated tumor and/or other diseases. The bifunctional molecular compound for inducing the degradation of the SHP2 protein based on the Cereblan ligand, or the pharmaceutically acceptable salt, hydrate or prodrug thereof is shown as the formula I, wherein L, B is shown as the claims and the specification.
Description
Technical Field
The invention relates to synthesis of a SHP2 protein targeted degradation agent, belonging to the technical field of pharmaceutical chemistry and biology. The compound can be used for preparing medicaments for treating SHP 2-mediated tumors and/or other diseases.
Background
SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene and expressed in various tissues and cells of the body. The current research shows that the mechanisms of SHP2 mediated tumorigenesis mainly include: activation of the RAS-ERK signaling pathway promotes survival and proliferation of cancer cells; after kinases such as MEK and the like are inhibited, SHP2 mediates compensatory activation pathways, thereby promoting the development of tumor drug resistance; as a downstream molecule of the PD-1 receptor, SHP2 is also involved in the transduction of T cell inhibitory signals, reducing tumor immune function. Therefore, targeted degradation of SHP2 could inhibit tumor cell growth, reduce tumor resistance, restore or enhance T cell-mediated anti-tumor immune function. (see: Ruess D.A., et al. Nat. Med.2018,24,954-
In recent years, people utilize proteasomes to have the function of specifically degrading protein substrates, provide a protein degradation target chimera (PROTAC) technology, and connect a target protein binding ligand and a ligand of ubiquitin ligase E3 through a connecting arm (Linker) by a chemical synthesis method to form a bifunctional molecular compound capable of spontaneously mediating the degradation of target proteins, so that the compound has a wide research value. However, the properties of the resulting compounds vary due to differences in the target protein ligand, the ligand of ubiquitin ligase E3 and the linker arm.
There is no report in the art that the SHP099 is used as a target protein binding ligand, and a diamine compound is used as a ligand of ubiquitin ligase E3 to obtain a bifunctional molecular compound mediating target protein degradation.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a compound capable of targeting and degrading SHP2 protein, and provides a very potential treatment scheme for SHP 2-mediated tumors and/or other diseases.
The specific technical scheme of the invention is as follows:
the invention provides a bifunctional molecular compound based on Cereblan ligand induced SHP2 protein degradation, or pharmaceutically acceptable salt, hydrate or prodrug thereof, as shown in formula I:
wherein:
b is a small molecular ligand of Cereblon protein in an E3 ubiquitin ligase complex, and is selected from thalidomide and derivatives thereof, lenalidomide and derivatives thereof, and pomalidomide and derivatives thereof;
b is any one of the following structures:
wherein:
w is selected from CH2、C＝O、SO2NH, N-C1-C4 alkyl;
x is selected from O, S;
z is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, halogen;
G. g' is selected from H, C1-C4 alkyl, -OH, C1-C4 alkyl substituted 5-10 member heterocyclyl containing 1-3 heteroatoms N, O or S;
R1selected from H, D, halogen, nitro, amino, cyano, hydroxy, C1-C4 alkyl, halogenated C1-C4 alkyl, deuterated C1-C4 alkyl.
Wherein L is connected with NH and B through covalent bonds,
the L is preferably any one of the structures shown below:
wherein: n is selected from an integer between 1 and 10.
The invention preferably selects the bifunctional molecular compound shown as the general formula II or the pharmaceutically acceptable salt, hydrate or prodrug thereof:
wherein:
R1selected from-H, -D, -F, -Cl, -Br, -I, -NO2、-CN、-NH2、-OH、-CH3、-CH2F、-CHF2、-CF3、-CH2D、-CHD2、-CD3、-CH2CH3；
L is any one of the following structures:
n is selected from an integer between 1 and 10.
The invention more preferably selects the bifunctional molecular compound shown as the general formula III or the pharmaceutically acceptable salt, hydrate or prodrug thereof:
wherein:
l is
n is selected from an integer between 2 and 5.
Preferred compounds of the invention include, but are not limited to:
according to the invention, pharmaceutically acceptable salts include the addition salts formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, succinic acid, and similar known acceptable acid salts.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. They may themselves have a weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) after administration.
The invention also provides a preparation method of the bifunctional molecule, which comprises the following steps:
n is selected from an integer between 1 and 10.
Step a: dissolving compound 1(SHP099) in appropriate amount of acetonitrile, adding bromopropyne into the reaction system under alkaline condition (such as potassium carbonate), heating and refluxing for a period of time, adding appropriate amount of water, extracting with ethyl acetate, collecting organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain compound 2;
step b: dissolving compound 3 (thalidomide derivative) in appropriate amount of DMF, adding appropriate amount of DIPEA into reaction system, reacting at 90 deg.C for a period of time, adding appropriate amount of water, extracting with ethyl acetate, collecting organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain compound 4n；
Step c: compound 2 and compound 4nIn THF/H2O1: 1(v/v) as solvent, by CuSO4The catalytic Click reaction is carried out for connection, and the compound SP is obtained after the silica gel column chromatography purificationn。
A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the above, or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, prodrug thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combination thereof.
Wherein the dosage form of the pharmaceutical composition is any one of injection, tablet and capsule.
The invention also provides the application of the compound and the pharmaceutically acceptable salt thereof or the composition in preparing medicaments for treating or preventing tumors.
The invention takes PROTAC technology as support, takes the prior SHP2 inhibitor (SHP099) as raw material, and synthesizes SHP2 proteolytic targeting chimeric molecules (SPn) with different Linker lengths. SHP099 is an allosteric inhibitor of SHP2, and has the advantages of high activity, good selectivity, and high oral bioavailability.
The present invention effectively targets and degrades SHP 2; similar to catalytic reaction, the medicament has low effective dose; only provides binding activity, is event-driven, is different from the traditional occupation drive, and does not need to directly inhibit the functional activity of the target protein; the drug does not require long-term and high-strength binding to the target protein. The SHP2 protein targeted degradation agent provides a novel treatment mode for treating SHP 2-mediated tumors and/or other diseases.
The invention evaluates the inhibiting activity of synthesized 4 PROTACs (SP2-SP5) and SHP099 on the SHP2 enzyme activity through an enzyme activity evaluation system, further verifies the biological activity of SP3 and SP4 and the targeted degradation activity of SHP2 protein through a cellular level, and considers that SP3 and SP4 can be used as targeted degradation agents of SHP2 protein, thereby providing a new treatment mode for treating SHP 2-mediated tumors and/or other diseases.
Wherein the tumor is any one of multiple myeloma, gastric cancer, lung cancer, breast cancer, esophageal cancer, colon cancer, medulloblastoma, acute myelogenous leukemia, chronic leukemia, melanoma, prostate cancer, hepatoma, renal cell tumor, cervical cancer, skin cancer, ovarian cancer, colon cancer, glioma, thyroid cancer and pancreatic cancer.
Drawings
FIG. 1 IC of SP2-SP5 and SHP099 on SHP2 enzyme activity inhibition50；
FIG. 2 the effect of SP2-SP5, as well as SHP099, Pomalidomide on Hela cell viability;
FIG. 3 shows the SP 4-mediated degradation characteristics of SHP2 protein in Hela cells.
A: degradation of SHP2 protein in Hela cells after 24 hours of SP4 action at different concentrations;
b: degradation of SHP2 protein in Hela cells after different concentrations of SP4 were applied for 48 hours;
c: degradation of SHP2 protein in Hela cells after 96 hours of SP4 action at different concentrations;
d: degradation of SHP2 protein after 100nM of SP4 for 0-96 h;
e: 2.5 μ M MG-132 reverses SP 4-mediated SHP2 proteolytic degradation;
FIG. 4SP4 degradation of SHP2 protein resulted in apoptosis of Hela cells.
A: the effect of different concentrations of SP4 on the levels of PARP, Bcl-xl, caspase-9, caspase-3 proteins in Hela cells;
b: effect of different concentrations of SP4 on JNK, Erk and p38 protein levels in Hela cells;
c: SP4 promotes apoptosis of Hela cells;
d: SP4 caused an S-phase arrest of the Hela cell cycle.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
EXAMPLE 1 Synthesis of Compound 2
100mg of Compound 1(SHP099) dissolved in 5mL CH3CN to which 24. mu.L of bromopropyne, 107mg of potassium carbonate powder and 21mg of K were added in this order under stirring2CO3Heating and refluxing for 6 hours, cooling the reaction solution, adding 30mL of water and 30mL of ethyl acetate, extracting, and collecting the organic layerDried over anhydrous sodium sulfate, concentrated to give the crude product, which was purified by silica gel column chromatography eluting with dichloromethane-methanol 40:1(v/v) to give 50.1mg of a yellow solid in 50% yield.
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.49(dd,J＝7.6,2.0Hz,1H),7.34–7.28(m,2H),4.22(s,2H),3.70–3.57(m,4H),3.44(d,J＝2.4Hz,2H),2.22(t,J＝2.4Hz,1H),1.69–1.62(m,4H),1.22(s,3H)；13C NMR(100MHz,CDCl3)δ154.1,150.4,139.9,134.2,132.9,130.8,130.6,128.4,125.8,119.7,83.6,71.6,51.8,41.3,36.9,31.6,25.4.
EXAMPLE 2 Compound 4nSynthesis of (n-4)
58mg of compound 3 (thalidomide derivative) (commercially available) was placed in a solanaceous flask, 3mL of DMF was added, 50mg of azido-PEG 4-amine (commercially available) and 47. mu.L of DIPEA were sequentially added with stirring, the mixture was reacted at 90 ℃ for 3 to 4 hours, 30mL of water and 30mL of ethyl acetate were added for extraction, the organic layer was dried over anhydrous sodium sulfate, the crude product was obtained by concentration, and the crude product was purified by silica gel column chromatography, and petroleum ether-ethyl acetate was eluted with a gradient of 1:2 to 1:4 to obtain 40.9mg of a yellow oily substance with a yield of 41%.
44 1H NMR(400MHz,CDCl3)δ8.81(br s,1H),7.48(dd,J＝8.0,7.2Hz,1H),7.09(d,J＝7.2Hz,1H),6.92(d,J＝8.8Hz,1H),6.49(t,J＝5.6Hz,1H),4.95–4.90(m,1H),3.72(t,J＝5.2Hz,2H),3.68–3.66(m,14H),3.48(q,J＝5.6Hz,2H),3.38(t,J＝5.0Hz,2H),2.88–2.72(m,3H),2.13–2.09(m,1H)；13C NMR(100MHz,CDCl3)δ171.6,169.4,168.8,167.8,146.9,136.1,132.6,116.9,111.7,110.3,70.8,70.74,70.71,70.7,70.65,70.62,70.1,69.6,50.8,48.9,42.5,31.5,22.9.
EXAMPLE 3 Compound 4nSynthesis of (n-2)
Specific operation and proportioning reference compound 4nPreparation of (n-4).
42Yellow oil, yield 40%.1H NMR(400MHz,CDCl3)δ9.06(br s,1H),7.49(t,J＝7.8Hz,1H),7.09(dd,J＝7.2,2.0Hz,1H),6.93(d,J＝8.4Hz,1H),6.50(t,J＝5.6Hz,1H),4.96–4.92(m,1H),3.74(t,J＝5.2Hz,2H),3.70–3.67(m,6H),3.48(q,J＝5.6Hz,2H),3.38(t,J＝4.4Hz,2H),2.80–2.73(m,3H),2.13–2.10(m,1H)；13C NMR(100MHz,CDCl3)δ171.7,169.4,168.8,167.7,146.9,136.1,132.6,116.9,111.6,110.3,70.75,70.72,70.1,69.6,50.7,48.9,42.4,31.5,22.8.
EXAMPLE 4 Compound 4nSynthesis of (n-3)
Specific operation and proportioning reference compound 4nPreparation of (n-4).
43Yellow oil, yield 40%.1H NMR(400MHz,CDCl3)δ8.85(br s,1H),7.43(dd,J＝8.4,7.2Hz,1H),7.04(d,J＝7.2Hz,1H),6.88(d,J＝8.4Hz,1H),6.44(t,J＝5.6Hz,1H),4.92–4.87(m,1H),3.68(t,J＝5.4Hz,2H),3.64–3.61(m,10H),3.43(q,J＝5.6Hz,2H),3.33(t,J＝5.0Hz,2H),2.83–2.68(m,3H),2.08–2.05(m,1H)；13C NMR(100MHz,CDCl3)δ171.7,169.4,168.8,167.7,146.9,136.1,132.5,116.9,111.6,110.3,70.7,70.0,69.5,50.7,48.9,42.4,31.5,22.8.
EXAMPLE 5 Compound 4nSynthesis of (n-5)
Specific operation and proportioning reference compound 4nPreparation of (n-4).
45Yellow oil, yield 42%.1H NMR(400MHz,CDCl3)δ8.82(br s,1H),7.48(dd,J＝8.0,7.2Hz,1H),7.09(d,J＝7.2Hz,1H),6.92(d,J＝8.8Hz,1H),6.49(t,J＝5.6Hz,1H),4.95–4.90(m,1H),3.72(t,J＝5.2Hz,2H),3.68–3.66(m,18H),3.49(q,J＝5.6Hz,2H),3.38(t,J＝5.0Hz,2H),2.88–2.72(m,3H),2.13–2.09(m,1H)；13C NMR(100MHz,CDCl3)δ171.6,169.4,168.7,167.8,146.9,136.1,132.6,116.9,111.7,110.3,70.8,70.72,70.71,70.6,70.5,70.1,69.6,50.8,48.9,42.5,31.5,22.9.
EXAMPLE 6 Final Compound SPnSynthesis of (n-4)
17.4mg of Compound 2 was dissolved in a mixed solution of 2mL of tetrahydrofuran and water (v/v ═ 1:1), and 23.3mg of Compound 4 was added thereto in this order with stirring49.0mg of copper sulfate and 23.8mg of sodium ascorbate, reacted at room temperature until the reaction was complete, 30mL of water and 30mL of ethyl acetate were added for extraction, the organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by silica gel column chromatography with dichloromethane: methanol (v/v ═ 40:1) gave 9mg of yellow solid in 22% yield.
SP4，1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.99(s,1H),8.22(s,1H),7.63–7.51(m,3H),7.37(t,J＝7.8Hz,1H),7.29(dd,J＝7.7,1.6Hz,1H),7.12(d,J＝8.6Hz,1H),7.02(d,J＝7.1Hz,1H),6.59(t,J＝5.8Hz,1H),5.69(s,1H),5.07–5.02(m,1H),4.58(t,J＝5.2Hz,2H),3.82(t,J＝5.2Hz,2H),3.59(t,J＝5.3Hz,2H),3.54–3.42(m,18H),2.97–2.76(m,2H),2.67–2.51(m,3H),2.34(d,J＝9.5Hz,2H),1.94(d,J＝33.1Hz,4H),1.54(s,3H)；13C NMR(100MHz,CDCl3)δ171.65,169.93,168.49,167.32,153.73,150.12,146.97,138.89,136.25,133.83,132.68,132.56,130.98,130.32,128.03,125.53,123.58,123.32,119.28,116.35,111.83,110.45,77.43,70.89,70.79,70.71,70.59,69.64,69.59,60.58,52.53,50.36,49.06,42.54,40.95,37.10,36.08,31.62,24.60,22.97,21.24,14.37.HRMS(ESI+):m/z calculated for C42H51Cl2N11O8[M+H]+,908.3372；found,908.3246.
EXAMPLE 7 Final Compound SPnSynthesis of (n-2)
Specific operation and proportioning reference compound SPnPreparation of (n-4).
SP2Yellow solid, yield 24%.1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.01(s,1H),8.21(s,1H),7.61(dd,J＝8.0,1.7Hz,1H),7.58–7.48(m,2H),7.38(t,J＝7.9Hz,1H),7.29(dd,J＝7.7,1.6Hz,1H),7.10(d,J＝8.5Hz,1H),7.01(d,J＝7.1Hz,1H),6.59(s,1H),5.69(s,1H),5.04(dd,J＝12.8,5.3Hz,1H),4.59(d,J＝5.4Hz,2H),3.84(t,J＝4.9Hz,2H),3.81–3.39(m,17H),2.31(s,2H),1.95(d,J＝44.1Hz,4H),1.53(s,3H)；13C NMR(100MHz,CDCl3)δ171.88,169.75,169.37,167.82,153.36,150.24,146.86,139.25,136.30,133.84,132.74,132.58,130.41,130.33,128.02,125.54,119.32,116.90,111.91,110.51,70.57,70.44,69.79,69.18,60.58,49.21,42.43,40.99,36.24,31.76,29.23,23.20,22.83,22.80,21.24,18.94,14.30,11.61.HRMS(ESI+):m/z calculated for C38H43Cl2N11O6[M+H]+,820.2848；found,820.2807.
EXAMPLE 8 Final Compound SPnSynthesis of (n-3)
Specific operation and proportioning reference compound SPnPreparation of (n-4).
SP3Yellow solid, yield 20%.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.95(s,1H),7.75–7.45(m,3H),7.45–7.19(m,2H),7.07(dd,J＝37.1,7.8Hz,2H),6.59(d,J＝6.1Hz,1H),5.61(s,1H),5.04(dd,J＝12.8,5.4Hz,1H),4.47(t,J＝5.2Hz,2H),4.10–3.37(m,19H),3.01–2.52(m,4H),2.14–1.86(m,2H),1.59(d,J＝47.7Hz,5H),1.29–1.12(m,3H)；13C NMR(100MHz,CDCl3)δ172.11,169.80,169.29,168.10,154.04,150.92,147.21,139.18,136.52,134.10,132.97,132.85,130.69,130.61,128.71,125.75,123.64,119.53,117.69,112.53,110.74,71.20,71.08,70.99,70.97,69.94,69.88,60.86,52.17,50.63,49.38,42.83,41.25,37.37,36.48,31.93,25.14,23.21,21.51,14.65.HRMS(ESI+):m/z calculated for C40H47Cl2N11O7[M+H]+,864.3110；found,864.3053.
EXAMPLE 9 Final Compound SPnSynthesis of (n-5)
Specific operation and proportioning reference compound SPnPreparation of (n-4).
SP5Yellow solid, yield 24%.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),7.951H NMR(400MHz,CDCl3)δ10.11(s,1H),8.96(s,1H),7.86–7.51(m,2H),7.46(ddd,J＝8.3,5.1,3.0Hz,2H),7.30(td,J＝7.2,1.9Hz,1H),7.07(d,J＝7.0Hz,1H),6.88(d,J＝8.5Hz,1H),6.48(s,1H),5.32(t,J＝4.9Hz,1H),4.89(dd,J＝11.6,5.5Hz,1H),4.63–4.17(m,4H),4.09(q,J＝7.2Hz,3H),3.93(s,1H),3.84(t,J＝5.2Hz,1H),3.76–3.40(m,20H),2.87–2.68(m,3H),2.19(t,J＝7.6Hz,4H),1.68(d,J＝49.8Hz,4H),1.23(s,3H)；13C NMR(100MHz,CDCl3)δ171.68,169.43,168.95,167.80,153.72,150.10,146.95,138.88,136.20,133.79,132.66,132.54,130.38,130.30,127.99,125.45,123.47,119.23,116.95,111.77,110.43,77.43,70.88,70.77,70.69,70.66,70.62,70.58,70.55,69.56,50.35,49.05,42.50,40.94,37.10,36.10,31.60,29.84,29.46,27.35,24.27,22.95,22.83,14.27.HRMS(ESI+):m/z calculated for C44H55Cl2N11O9[M+H]+,952.3634；found,952.3704.
EXAMPLE 10 cloning, expression and purification of SHP2 protein
Human SHP2(NCBI RefSeq NP-002825.3) was cloned into pet30a,expressed in E.coli BL21Star (DE 3). BL21 strain transfected with the recombinant plasmid was cultured at 37 ℃ for 3-4h, followed by addition of 1mM IPTG to promote protein expression at 18 ℃. After overnight growth at 18 ℃ the bacteria were collected by centrifugation at 3000g for 10 min. Bacteria were lysed in lysis buffer (50mM Tris-HCl, pH 8.5,25mM imidazole, 500mM NaCl,2.5mM MgCl)21mM TCEP,1mM PMSF), centrifuging at 40000g for 1h, and collecting the supernatant as a crude protein product. And adding a 4M imidazole solution into the crude protein product until the final concentration is 0.10M, and purifying the target protein by using an AKTA Pure protein purification system. Before loading the sample, the Ni-NTA affinity chromatographic column is balanced by Binding buffer. The supernatant was then passed through an affinity column at the same flow rate to allow the target protein containing 6-His tag to be bound well to the Ni-NTA Agarose affinity column. After the sample loading is finished, the column is flushed by using Binding buffer. Elution was again performed using an Elution buffer.
Binding buffer formula: 50mM Tris-HCl,500mM NaCl,25mM imidazole
Elution buffer formula: the protein solution of interest was transferred to a 30kDa protein concentration tube with 50mM Tris-HCl,500mM NaCl,200mM imidazole, concentrated to 5mL at 4 ℃ at 3000rpm, and then the imidazole in the protein solution was replaced with a size exclusion chromatography elution system (200mM NaCl,20 mM Tris-HCl pH 8.80). And (3) further purifying the target protein by using an AKTA Pure protein purification system and selecting a molecular exclusion chromatographic column.
Example 11 in vitro enzyme inhibition assay
To 50. mu.l of buffer (60mM HEPES, pH 7.2,75mM KCl,75mM NaCl,5mM DTT, 0.05% Triton-X100,1mM EDTA) were added 2.5nM SHP2 protein and 0.5M diphosphorylated IRS1 polypeptide and compounds (SP2-SP5 and SHP099) at various concentrations, and after incubation at 25 ℃ for 60min, 2.5mM DiFMUP was added and fluorescence signal was detected with a microplate reader (SpectraMax M5e plate read), and Ex/Em. 340/450nM was detected once per minute for 30 total assays. IC calculation of SP2, SP3, SP4, SP5 Using GraphPad Prism50The values were 0.306. mu.M, 0.945. mu.M, 0.714. mu.M, 1.084. mu.M, respectively. The results show that SP2-SP5 has a moderate SHP2 protein inhibition activity, suggesting that the action mechanism may be changed, such as from space occupying inhibition to targeted degradation.
Example 12 detection of cell viability by CCK8 method
Hela cells grown in logarithmic phase were taken, trypsinized, plated in 96-well plates at a density of 5000 cells/well, and after 24h, treated with different concentration gradients (0-200. mu.M) of SP2-SP5, SHP099, and Pomalidomide. Viable cell numbers were measured 24h after dosing with CCK-8 at 450nm wavelength. The results show that SP3 and SP4 have strong inhibition effect on the growth of Hela cells, and SP2, SP3, SP4 and SP5 have different growth inhibition effects on Hela cells, in particular SP3 and SP4, and the IC thereof50The values are 5.77nM and 4.30nM, respectively, and the activity is increased by about 100 times.
Example 13 Effect of different concentrations of SP4 on the levels of PARP, bcl-xl, caspase-9, caspase-3, JNK, Erk and p38 proteins in Hela cells
1. Extraction of HeLa cell Total protein samples administered with different concentrations of SP4
(1) And collecting Hela cells in the six-hole plate by using a cell scraper, and centrifuging at a low speed to obtain cell sediment.
(2) PMSF was added to an appropriate amount of RIPA lysate (medium) and mixed well to a final concentration of 1 mM.
(3) Adding 40 μ L of lysis solution into the cell precipitate, blowing with a gun head, placing on ice for lysis, and vortexing once every 10min for 30 min. After the completion of lysis, the cells were centrifuged at 14000rpm for 10min at 4 ℃ and the precipitate was discarded, and the supernatant was collected.
Determination of Total protein concentration by BCA method
(1) Preparation of protein standards: the protein standard (5mg/mL) was completely dissolved, and 10. mu.L of the solution was diluted to 100. mu.L to give a final concentration of 0.50 mg/mL.
(2) Adding standard substance into standard substance well of 96-well plate according to 0,1, 2, 4, 8, 12, 16, 20 μ L, respectively, adding standard substance diluent to make up to 20 μ L, that is, standard substance concentration is 0, 0.025, 0.05, 0.10, 0.20, 0.30, 0.40, 0.50mg/mL, respectively.
(3) And adding 20 mu L of protein sample to be detected into sample holes of a 96-well plate.
(4) 200. mu.L of BCA working solution was added to each well, and the mixture was left at 37 ℃ for 20 min. If the protein concentration is low, the incubation time may be suitably prolonged or the incubation temperature may be increased.
(5) The absorbance at 562nm of each well was measured using a microplate reader.
(6) And drawing a standard curve, and calculating the protein concentration of the sample according to the standard curve.
3. Electrophoresis
The electrophoresis current was set at 200mA, and the electrophoresis time was 120 min. The protein concentration is calculated according to the BCA method when the sample is loaded, so that the loading amount of the sample in each well is 40 mu g.
Western Blot membrane transfer
After the electrophoresis is finished, the porous pad, the filter paper, the PVDF membrane (activated by methanol in advance), the gel, the filter paper and the porous pad are placed into a membrane rotating instrument in sequence from the anode to the cathode, and the membrane is rotated by constant current of 120 mA. No significant air bubbles can be present between the interlayers.
5. Immunoassay
(1) And (3) sealing: after confirming that the membrane transfer is successful, taking out the PVDF membrane, washing with TBST, adding 5% skimmed milk powder, gently shaking at room temperature for 30min, and blocking the nonspecific protein.
(2) Antigen-antibody specific reaction: PARP, bcl-xl, caspase-9, caspase-3, JNK, Erk, p38 and internal reference antibody beta-actin were added separately and incubated overnight at 4 ℃. The membrane was then gently shaken 3 times with PBST for 15min each. HRP enzyme-labeled IgG secondary antibody (1:1500) was added, gently shaken at room temperature for 2h, and washed 3 times with PBST for 15min each. (3) ECL development: and (3) placing the PVDF membrane in an ECL chemiluminescence reagent for reaction for 1-2 min. Developing and fixing by a conventional method.
(4) Quantitative analysis: the gel imaging system scans and analyzes the optical density values (OD values) of the bands. The ratio of the OD value of each protein band to the OD value of the internal reference beta-actin band was calculated and expressed after the control group was set to 1 for calibration.
The results show that SP4 causes a decrease in the levels of PARP, bcl-xl, caspase-9, caspase-3 in a dose-dependent manner, suggesting that it activates caspases to cause apoptosis. Meanwhile, SP4 can inhibit JNK, Erk, p38 active form, indicating that SP4 inhibits RAS/MAPK signal transduction and cell response by inhibiting catalytic activity of SHP 2.
Example 14 SP 4-mediated degradation of SHP2 protein in Hela cells
(1) Hela cells in log phase were grown in fresh medium to a concentration of 2X 105Mixing the cell suspension solution with the cell suspension solution of/mL, and adding the cell suspension solution into a 6-hole plate;
(2) adding SP4 with different concentrations (100000,3333.3,1111.1,370.4,123.5,41.2,13.7,4.6,1.5,0.5 and 0nM) after the cells adhere to the wall, and centrifuging and collecting the cells after 24,48 and 96 hours of treatment;
or adding 100nM SP4 after the cells adhere to the wall, and centrifugally collecting the cells after 0,12,24,48,72 and 96 hours of each treatment;
③ after the cells adhere to the wall, adding 0.0 mu M or 2.5 mu M mg132 to pretreat the cells for 12 hours, then adding SP4 with different concentrations (13.7,4.6 and 0nM), and after 48 hours of treatment, centrifuging and collecting the cells;
(4) the cells collected in (2) were run in a western manner as described in example 13, and the degradation of the SHP2 protein was detected using the SHP2 antibody.
The results show that SP4 significantly reduces the level of SHP2 protein in Hela cells in a time-dependent manner, and in addition, a proteasome inhibitor MG-132 can completely block the process, which indicates that SP4 has the function of specifically inducing the degradation of SHP2 protein through a proteasome pathway.
Example 15 SP4 promotes apoptosis of Hela cells
(1) Hela cells in log phase were grown in fresh medium to a concentration of 2X 105The preparation method comprises the following steps of uniformly mixing a/mL cell suspension, adding the cell suspension into a 6-well plate, and adding medicines (SP4 and SHP099) with different concentrations for treatment after the cells adhere to the wall.
(2) After culturing in an incubator for 24 hours, centrifugally collecting cells;
(3) sucking supernatant, adding precooled PBS, gently mixing, transferring to a flow tube for centrifugation, removing PBS, and then properly dispersing cells to avoid cell agglomeration;
(4) adding 500 mu L Binding Buffer to each tube for resuspending cells, fully mixing uniformly, adding 5 mu L annexin V-FITC solution and 5 mu L PI solution, lightly mixing uniformly, and reacting for 10 minutes in a dark place at normal temperature to fully dye the two fluorescent dyes;
(5) detection was performed by flow cytometry at 488nm excitation wavelength, FITC fluorescence was detected by a 515nm channel filter, PI fluorescence was detected by another channel filter at a wavelength greater than 560nm, and data was analyzed by the associated software.
The results show that SP4 has better pro-Hela apoptosis activity than SHP 099. 100nM SP4 caused apoptosis in 54.01% of cells compared to the control (0.13%), while 1000nM SHP099 caused apoptosis in only 33.74%.
Example 16 SP4 causes an S phase arrest in the Hela cell cycle
(1) Hela cells in log phase were grown in fresh medium to a concentration of 2X 105The preparation method comprises the following steps of uniformly mixing a/mL cell suspension, adding the cell suspension into a 6-well plate, and adding medicines (SP4 and SHP099) with different concentrations for treatment after the cells adhere to the wall.
(2) After culturing in an incubator for 24 hours, centrifugally collecting cells, and washing for 3 times by PBS;
(3) 1mL of precooled 70% ethanol is added, the mixture is gently blown and uniformly mixed, and the mixture is fixed for 2 hours at 4 ℃.
(4) Dyeing: 0.5mL of propidium iodide staining solution was added to each tube of cell sample, the cell pellet was slowly and thoroughly resuspended, and incubated at 37 ℃ in the dark for 30 minutes to complete the flow assay. The red fluorescence was detected with a flow cytometer at the 488nm excitation wavelength, with the light scattering detected. Cellular DNA content analysis and light scattering analysis were performed using appropriate analysis software.
The results show that SP4 can cause Hela cells to generate cell cycle arrest in S phase.
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