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Purity: ≥98%
BAY-293 (BAY293) is a novel, potent, cell-active small-molecule SOS1 inhibitor with anticancer activity. It functions by preventing RAS activation by interfering with the RAS-SOS1 interaction, with an IC50 of 21 nM. Using a KRASG12C–SOS1cat NMR fragment-based screening assay, BAY-293 was discovered, and it effectively interferes with the interaction of KRAS and its exchange factor SOS1. Since the late 1980s, it has been known that significant oncogenes with a high frequency of occurrence in human cancers are mutations in the RAS genes. Due to these mutations, the small GTPase RAS is less able to hydrolyze GTP, which maintains this molecular switch in a constitutively active GTP-bound form that uncontrollably triggers oncogenic downstream signaling. Guanine nucleotide exchange factors, which enable RAS to cycle from the inactive GDP-bound state to the active GTP-bound form, are one tactic to lower the levels of active RAS. Using the crystal structures of KRASG12C-SOS1, SOS1, and SOS2, the binding sites, mechanism of action, and selectivity were determined. These inhibitors inhibit the reloading of KRAS with GTP, which results in antiproliferative activity, by preventing the formation of the KRAS-SOS1 complex. With an IC50 of 21 nM, compound 23 (BAY-293) is the last one to selectively inhibit the KRAS-SOS1 interaction. It is a useful chemical probe for further studies.
| Targets |
KRAS-SOS1 ( IC50 = 21 nM )
BAY-293 suppresses the activation of RAS in HeLa cells with IC50 values in the submicromolar range[1]. BAY-293 (595 nM-3580 nM; 72 hours) demonstrates efficient antiproliferative activity against KRAS cell lines carrying the wild-type mutation (K-562, MOLM-13) as well as those carrying the KRASG12C mutation (NCI-H358, Calu-1)[1]. BAY-293 effectively reduces the levels of pERK in K-562 cells without changing the amount of ERK protein overall[1]. |
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| ln Vitro |
BAY-293 suppresses the activation of RAS in HeLa cells with IC50 values in the submicromolar range[1].
BAY-293 (595 nM-3580 nM; 72 hours) demonstrates efficient antiproliferative activity against KRAS cell lines carrying the wild-type mutation (K-562, MOLM-13) as well as those carrying the KRASG12C mutation (NCI-H358, Calu-1)[1]. BAY-293 effectively reduces the levels of pERK in K-562 cells without changing the amount of ERK protein overall[1]. BAY-293 (compound 23) potently and selectively inhibits the interaction between KRASG12C and its exchange factor SOS1, with an IC50 of 21 nM in a biochemical interaction assay. [1] Isothermal titration calorimetry (ITC) confirmed direct binding to the catalytic domain of SOS1 (SOS1cat) with a dissociation constant (KD) of 36 nM. [1] Thermal shift assay (TSA) confirmed binding and stabilization of SOS1cat by BAY-293. [1] Native mass spectrometry (Native MS) analysis showed a 1:1 stoichiometry of BAY-293 binding to SOS1cat with a mass shift of 449 Da. [1] BAY-293 disrupts the KRAS-SOS1 interaction, as demonstrated by reduced FRET signal in an interaction assay and reduced binding of KRASG12C to immobilized SOS1cat in a surface plasmon resonance (SPR) assay. [1] The compound demonstrates high selectivity for SOS1 over the closely related isoform SOS2, attributed to a key histidine-to-valine substitution in SOS2 that prevents a crucial stacking interaction. [1] BAY-293 showed no inhibitory activity (IC50 > 20,000 nM) against a large panel of kinases, including EGFR and all kinases of the RAS-RAF-MEK-ERK pathway, confirming its selectivity as a non-kinase inhibitor. [1] |
| ln Vivo |
BAY-293, an SOS1/Ras inhibitor was discovered to suppress colony formation and proliferation in resistant and BCR-ABL independent chronic myeloid leukemia cells.
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| Enzyme Assay |
Biochemical SOS1 Inhibition Assays: Two HTRF (Homogeneous Time-Resolved Fluorescence) assays were used. The "On-assay" quantified SOS1-mediated loading of a fluorescently labeled GTP analog onto KRASG12C, resulting in an increased HTRF signal. The secondary "Off-assay" monitored the SOS1-catalyzed decrease in HTRF signal due to the deloading of a fluorescently tagged GDP analog preloaded onto KRASG12C. Hits were tested in both assays to exclude artifacts and GTP-competitive compounds. [1]
KRAS-SOS1 Interaction Assay: An HTRF-based assay was used to directly quantify the equilibrium binding interaction between KRASG12C and SOS1cat. Compounds that disrupted the complex led to a decreased FRET signal. [1] Selectivity Assays: Compound effects on intrinsic nucleotide exchange of KRASG12C (in the absence of SOS1) and on the nucleotide exchange of another small GTPase (CDC42) by its GEF DBS were tested to confirm SOS1-specific activity. Interaction with the RAS binding domain (RBD) of the downstream effector CRAF was also assessed. [1] |
| Cell Assay |
Cell Line: K-562, MOLM-13, H358 and Calu-1 cell lines
Concentration: 595-3580 nM Incubation Time: 72 hours Result: IC50s of 1,090±170 nM, 995±400 nM, 3,480±100 nM and 3,190±50 nM for K-562, MOLM-13, H358 and Calu-1 cells, respectively. Active RAS Quantification: HeLa cells were incubated with BAY-293, and the amount of activated, GTP-loaded total RAS was quantified from cellular lysates using a pull-down assay. BAY-293 inhibited RAS activation with an IC50 in the submicromolar range. [1] Phospho-ERK (pERK) Analysis: Levels of phosphorylated ERK (pERK), a downstream readout of RAS pathway activation, were quantified in K-562 cells (wild-type KRAS) and Calu-1 cells (homozygous KRASG12C mutant) after compound incubation. BAY-293 efficiently inhibited pERK levels in K-562 cells. In Calu-1 cells, it reduced pERK levels by approximately 50% after 24-hour treatment, indicating partial pathway inhibition in a mutant KRAS context. [1] Antiproliferative Assays: Cell viability was assessed using cell lines with wild-type KRAS (K-562, MOLM-13) and mutant KRASG12C (NCI-H358, Calu-1). BAY-293 showed antiproliferative activity with IC50 values ranging from approximately 1,000 nM to 3,500 nM across these cell lines. [1] Combination Study: The antiproliferative effect of BAY-293 in combination with the covalent KRASG12C inhibitor ARS-853 was assessed in NCI-H358 cells (heterozygous KRASG12C). Synergy was evaluated using isobologram analysis and the Chou-Talalay combination index method, revealing synergistic antiproliferative activity. [1] |
| References | |
| Additional Infomation |
BAY-293 is the (R)-enantiomer of racemic compound 22. [1] It was discovered through a structure-based drug design approach that integrates high-throughput screening (HTS) and fragment-based screening for lead compounds targeting the KRAS-SOS1 complex. [1] The compound binds to a surface pocket near the KRAS binding site on SOS1. Its mechanism of action is to disrupt the KRAS-SOS1 interaction through steric hindrance and indirect influence on the conformation of the Tyr884 side chain of SOS1 residue. [1]
The crystal structure of the SOS1-BAY-293 complex has been resolved, revealing key interactions: the quinazoline core stacks with His905 and Tyr884; the central aniline NH forms a hydrogen bond with Asn879; the side-chain amino groups form two hydrogen bonds with Asp887 and Tyr884, and interact with Tyr884 via a cation-π interaction. [1] This study suggests that inhibiting SOS1 is a viable strategy for targeting RAS-driven tumors, particularly suitable for use in combination with direct KRAS inhibitors in KRAS-mutant cancers. [1] BAY-293 is considered a valuable chemical probe for future in vitro studies of the biological properties of RAS-SOS1. The study indicates that improving its bioavailability is crucial for in vivo studies. [1] |
| Molecular Formula |
C25H28N4O2S
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|---|---|
| Molecular Weight |
448.5804
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| Exact Mass |
448.19
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| Elemental Analysis |
C, 66.94; H, 6.29; N, 12.49; O, 7.13; S, 7.15
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| CAS # |
2244904-70-7
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| Related CAS # |
(S)-BAY-293; 2244904-69-4
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| PubChem CID |
137322663
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| Appearance |
White to light yellow solid powder
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| LogP |
4.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
584
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=NC2=CC(=C(C=C2C(=N1)N[C@H](C)C3=CC(=CS3)C4=CC=CC=C4CNC)OC)OC
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| InChi Key |
WEGLOYDTDILXDA-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C25H28N4O2S/c1-15(24-10-18(14-32-24)19-9-7-6-8-17(19)13-26-3)27-25-20-11-22(30-4)23(31-5)12-21(20)28-16(2)29-25/h6-12,14-15,26H,13H2,1-5H3,(H,27,28,29)/t15-/m1/s1
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| Chemical Name |
6,7-dimethoxy-2-methyl-N-[(1R)-1-[4-[2-(methylaminomethyl)phenyl]thiophen-2-yl]ethyl]quinazolin-4-amine
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| Synonyms |
BAY293; BAY 293; BAY-293
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~90 mg/mL (~200.6 mM)
Ethanol: ~90 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
KRASG12C–SOS1catNMR fragment screen.Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. |
Discovery of quinazolines as direct SOS1 inhibitors that disrupt the KRAS–SOS1 complex.Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. |
Cellular characterization of compounds22to24,compound 23 (BAY-293).Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. |
SOS1–compound1cocrystal structure, SAR, and crystal structure of SOS2.Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. |
Structure-based linking of the fragment and HTS hits.Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. |
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