BAY-293
(Synonyms: (R)-6,7-二甲氧基-2-甲基-N-(1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)喹唑啉-4-胺) 目录号 : GC33186
An inhibitor of the K-Ras-SOS1 protein-protein interaction
Cas No.:2244904-70-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BAY-293 is an inhibitor of the protein-protein interaction between K-Ras and the guanine nucleotide exchange factor son of sevenless homolog 1 (SOS1; IC50 = 0.021 ?M).1 It inhibits proliferation of K562 and MOLM-13 cells expressing wild-type K-Ras, as well as NCI H358 and Calu-1 cells expressing mutant K-RasG12C with IC50 values of 1.09, 0.995, 3.48, and 3.19 ?M, respectively.
1.Hillig, R.C., Sautier, B., Schroeder, J., et al.Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interactionProc. Natl. Acad. Sci. USA116(7)2551-2560(2019)
| Cas No. | 2244904-70-7 | SDF | |
| 别名 | (R)-6,7-二甲氧基-2-甲基-N-(1-(4-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)喹唑啉-4-胺 | ||
| Canonical SMILES | COC1=C(OC)C=C(N=C(C)N=C2N[C@H](C)C3=CC(C4=C(CNC)C=CC=C4)=CS3)C2=C1 | ||
| 分子式 | C25H28N4O2S | 分子量 | 448.58 |
| 溶解度 | DMSO : ≥ 125 mg/mL (278.66 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2293 mL | 11.1463 mL | 22.2926 mL |
| 5 mM | 0.4459 mL | 2.2293 mL | 4.4585 mL |
| 10 mM | 0.2229 mL | 1.1146 mL | 2.2293 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines
Discov Oncol 2022 Sep 1;13(1):84.PMID:36048281DOI:10.1007/s12672-022-00550-w.
KRAS is mutated in approximately 25% of cancer patients and first KRAS G12C-specific inhibitors showed promising responses. Pancreatic cancer has the highest frequency of KRAS mutations but the prevailing KRAS G12D mutation is difficult to target. Inhibition of the GTP exchange factor (GEF) SOS1-KRAS interaction impairs oncogenic signaling independently of the specific KRAS mutations. In general, cell lines exhibiting KRAS mutations show specific alterations in respect to glucose utilization, signal transduction and stress survival. The aim of this investigation was to check the putative synergy of the SOS1 inhibitor BAY-293 with modulators targeting specific vulnerabilities of KRAS-mutated cell lines in vitro. The cytotoxicity of BAY-293 combinations was tested against MIA PaCa-2 (G12C), AsPC1 (G12D) and BxPC3 (KRAS wildtype) cell lines using MTT tests and calculation of the combination indices (CI) according to the Chou-Talalay method. The results show that BAY-293 synergizes with modulators of glucose utilization, inhibitors of the downstream MAPK pathway and several chemotherapeutics in dependence of the specific KRAS status of the cell lines. In particular, divergent responses for BAY-293 combinations between pancreatic and NSCLC cell lines were observed for linsitinib, superior inhibitory effects of trametinib and PD98059 in NSCLC, and lack of activity with doxorubicin in case of the pancreatic cell lines. Phosphoproteome analysis revealed inhibition of distinct signaling pathways by BAY-293 for MIA PaCa-2 on the one hand and for Aspc1 and BH1362 on the other hand. In conclusion, BAY-293 exhibits synergy with drugs in dependence of the tumor type and specific KRAS mutation.
Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction
Proc Natl Acad Sci U S A 2019 Feb 12;116(7):2551-2560.PMID:30683722DOI:10.1073/pnas.1812963116.
Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRASG12C-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations.
Cytotoxicity of combinations of the pan-KRAS inhibitor BAY-293 against primary non-small lung cancer cells
Transl Oncol 2021 Dec;14(12):101230.PMID:34598083DOI:10.1016/j.tranon.2021.101230.
KRAS is mutated in approximately 25% of Non-small Cell Lung Cancer (NSCLC) patients and first specific inhibitors showed promising responses that may be improved by concurrent interference with downstream signaling pathways. Cell lines exhibiting KRAS mutations show specific sensitivities to modulators affecting glucose utilization, signal transduction and cell survival. Novel SOS1-directed inhibitors with a broader anticancer coverage such as BAY-293 and BI-3406 inhibit KRAS through the hindrance of SOS1-KRAS interactions. The aim of this study was to check the putative synergy of BAY-293 with modulators having revealed specific vulnerabilities of KRAS-mutated cell lines. The present investigation tested the cytotoxicity of BAY-293 combinations against a series of Osimertinib-resistant primary NSCLC cell lines using MTT tests and calculation of combination indices according to the Chou-Talalay method. The results show that BAY-293 synergizes with modulators of glucose metabolism, inhibitors of cellular proliferation, several chemotherapeutics and a range of diverse modulators, thus corroborating the chemosensitivities of cells expressing mutated KRAS. In conclusion, BAY-293 exerts cytotoxicity with a wide range of drugs against Osimertinib-resistant primary NSCLC cell lines. The administration of pan-KRAS inhibitors alone may be limited in vivo by toxicity to normal tissues but made feasible by its use as part of suitable drug combinations. This study shows that BAY-293 combinations are active against NSCLC cells not further amenable to mutated EGFR-directed targeted therapy and results likewise hold relevance for pancreatic and colon cancer.
Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma
Acta Pharmacol Sin 2022 Oct;43(10):2696-2708.PMID:PMC9525295DOI:10.1038/s41401-022-00897-4.
Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most lethal cancers worldwide. Several basic studies have confirmed that Kirsten rat sarcoma virus (KRAS) is a key driver gene for the occurrence of PDAC, and KRAS mutations have also been found in most patients in clinical studies. In this study, two pan-KRAS inhibitors, BI-2852 and BAY-293, were chosen as chemical probes to investigate their antitumor potency in PDAC. Their inhibitory effects on KRAS activation were validated in vitro and their antiproliferative potency in PDAC cell lines were profiled, with half-maximal inhibitory concentration (IC50) values of approximately 1 μM, demonstrating the therapeutic potential of pan-KRAS inhibitors in the treatment of PDAC. However, feedback regulation in the KRAS pathway weakened inhibitor activity, which was observed by a 50 times difference in BAY-293 from in vitro activity. Furthermore, pan-KRAS inhibitors effectively inhibited cell proliferation in 3D organoids cultured from PDAC patient samples; however, there were some variations between individuals. These results provide a sufficient theoretical foundation for KRAS as a clinical therapeutic target and for the application of pan-KRAS inhibitors in the treatment of PDAC, with important scientific significance in translational medicine.
Targeting SOS1 overcomes imatinib resistance with BCR-ABL independence through uptake transporter SLC22A4 in CML
Mol Ther Oncolytics 2021 Nov 20;23:560-570.PMID:34938856DOI:10.1016/j.omto.2021.11.010.
Resistance to the BCR-ABL inhibitor imatinib mesylate poses a major problem for the treatment of chronic myeloid leukemia. Imatinib resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, sometimes there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent imatinib mesylate resistance remains to be elucidated. SOS1, a guanine nucleotide exchange factor for Ras protein, affects drug sensitivity and resistance to imatinib. The depletion of SOS1 markedly inhibits cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulates the expression of SLC22A4, a member of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that intracellular accumulation of imatinib is accompanied by upregulation of SLC22A4 through SOS1 inhibition in both sensitive and resistant chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in chronic myeloid leukemia cells with resistance and BCR-ABL independence. Altogether these findings indicate that targeting SOS1 inhibition promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport.