 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C63H88F3N11O7 |
| Molecular Weight | 1168.43754577637 |
| Exact Mass | 1167.682 |
| Elemental Analysis | C, 64.76; H, 7.59; F, 4.88; N, 13.19; O, 9.58 |
| CAS # | 2922732-54-3 |
| PubChem CID | 168201327 |
| Appearance | White to off-white solid powder |
| LogP | 7.2 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 17 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 84 |
| Complexity | 2370 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | C[C@@H](C1=C(C=C(C=N1)N2CCN(CC2)C3CC3)C4=C5CC(COC(=O)[C@@H]6CCCN(N6)C(=O)[C@H](C[C@H]7CN(CCO7)C8=CC5=C(N4CC(F)(F)F)C=C8)NC(=O)[C@H](C9CCCC9)N1CC[C@@]2(C1)CCN(C2)C(=O)[C@H]1[C@H](N1C)C1CC1)(C)C)OC |
| InChi Key | VKNNQJWNUPSOEK-VCAAAJMFSA-N |
| InChi Code | InChI=1S/C63H88F3N11O7/c1-39(82-5)52-47(30-44(33-67-52)72-25-23-71(24-26-72)42-14-15-42)55-48-32-61(2,3)38-84-60(81)49-11-8-20-77(69-49)58(79)50(31-45-34-73(27-28-83-45)43-16-17-51(46(48)29-43)76(55)37-63(64,65)66)68-57(78)54(40-9-6-7-10-40)74-21-18-62(35-74)19-22-75(36-62)59(80)56-53(70(56)4)41-12-13-41/h16-17,29-30,33,39-42,45,49-50,53-54,56,69H,6-15,18-28,31-32,34-38H2,1-5H3,(H,68,78)/t39-,45-,49-,50-,53+,54-,56+,62-,70?/m0/s1 |
| Chemical Name | (2S)-2-cyclopentyl-2-[(5S)-2-[(2R,3R)-3-cyclopropyl-1-methylaziridine-2-carbonyl]-2,7-diazaspiro[4.4]nonan-7-yl]-N-[(6S,8S,14S)-21-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]acetamide |
| Synonyms | KRAS G12D inhibitor 18; 2922732-54-3; SCHEMBL26348957; RMC9805; RMC-9805; RMI-5921; 2922732-54-3; RMC 9805; Zoldonrasib; zoldonrasib [INN]; XJ52BWK3XE; SCHEMBL26348957; |
| 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
| Targets | KRAS(G12D); Zoldonrasib (RMC-9805) is a first-in-class, mutant-selective, covalent inhibitor targeting KRAS G12D (ON state). It binds irreversibly to the GDP-bound (inactive) form of KRAS G12D, locking it in an inactive conformation. [2] |
| ln Vitro |
RMC-9805 is a small molecule compound that targets KRASG12D oncoproteins selectively via forming a covalent tri-complex RAS(ON). RMC-9805 has been shown to inhibit RAS signaling in KRASG12D mutant cancer cells and induce apoptosis. RMC-9805 also decreased the secretion of immunosuppressive cytokines by KRASG12D tumor cells, while promoting the secretion of lymphocyte-recruiting factors [2]. RMC-9805 demonstrated potent inhibition of KRAS G12D signaling in cell-based assays, leading to suppression of downstream ERK phosphorylation (p-ERK) and induction of apoptosis in KRAS G12D-mutant cancer cell lines. [2] In proliferation assays, RMC-9805 showed selective cytotoxicity against KRAS G12D-mutant cells compared to wild-type KRAS or other KRAS-mutant variants. [2] |
| ln Vivo |
Oral administration of RMC-9805 drove durable complete responses and synergized with anti-PD-1 in an immune-infiltrated colorectal KRASG12D mutant model. Re-challenge experiments further demonstrated that RMC-9805 induced immunological memory. The activity of RMC-9805 was also assessed in an orthotopic, immune-evasive, GEMM-derived preclinical model for PDAC, where it induced a profound and sustained inhibition of RAS signaling, driving initial tumor regressions and significantly prolonging survival.
Tumors treated with RMC-9805 in vivo showed significant transformation of the TME in favor of anti-tumor immunity, with an increase in T cell infiltration and decrease in immunosuppressive myeloid cells, including M2-like macrophages and MDSCs. RMC-9805 also modulated expression of cancer cell surface proteins, notably decreasing expression of immune checkpoint molecules while significantly increasing MHC-I expression. TCR sequencing of T cells from tumors and blood harvested from treated mice revealed a significant increase in T cell diversity, as well as an increase in the number of shared TCR clones among all KRASG12D(ON) inhibitor-treated samples, suggesting cancer-associated antigen recognition. Overall, in these preclinical experiments, RMC-9805 exhibited direct anti-tumor effects and indirectly transformed the TME through inhibition of cancer cell-intrinsic KRASG12D oncogenic signaling. The increased antigen presentation, recognition, and T cell infiltration induced by inhibition of mutant KRAS may permit a more favorable environment for immune-directed ‘companion’ therapies, such as checkpoint inhibitors, cellular therapies, and/or vaccines [2]. In preclinical xenograft models, oral administration of RMC-9805 led to significant tumor regression in KRAS G12D-driven cancers. Combination with immune checkpoint inhibitors (e.g., anti-PD-1) enhanced antitumor efficacy, suggesting potential synergy with immunotherapy. [2] |
| Cell Assay |
In preclinical xenograft models, oral administration of RMC-9805 led to significant tumor regression in KRAS G12D-driven cancers. Combination with immune checkpoint inhibitors (e.g., anti-PD-1) enhanced antitumor efficacy, suggesting potential synergy with immunotherapy. [2] |
| Animal Protocol |
In mouse xenograft studies, RMC-9805 was administered orally (formulation details not specified) at defined doses. Tumor growth inhibition and pharmacodynamic markers (e.g., p-ERK suppression) were monitored. [2] |
| ADME/Pharmacokinetics |
RMC-9805 exhibited favorable oral bioavailability and sustained target engagement in preclinical species. Detailed PK parameters (e.g., half-life, Cmax) were not disclosed. [2] |
| Toxicity/Toxicokinetics |
No significant toxicity was reported in preclinical models at efficacious doses. Further safety assessments (e.g., maximum tolerated dose) were not detailed. [2] |
| References |
[1]. Preparation of peptide-linked macrocyclic dipeptides as Ras inhibitors.World Intellectual Property Organization, WO2023060253 A1 2023-04-13. [2]. RMC-9805, a first-in-class, mutant-selective, covalent and orally bioavailable KRASG12D(ON) inhibitor, promotes cancer-associated neoantigen recognition and synergizes with immunotherapy in preclinical models. Cancer Res 1 April 2023; 83 (7_Supplement): 3475. |
| Additional Infomation |
RMC-9805 represents a novel covalent inhibitor class targeting KRAS G12D(ON), distinct from earlier KRAS(G12C) inhibitors. Its mechanism involves trapping KRAS G12D in an inactive state, impairing downstream signaling. [2] Preclinical data suggest potential for combination with immunotherapy due to enhanced neoantigen presentation. [2] Zoldonrasib is an orally bioavailable covalent tri-complex inhibitor of the oncogenic KRAS substitution mutation G12D, with potential antineoplastic activity. Upon oral administration, zoldonrasib specifically targets and non-covalently binds to cyclophilin A to form a non-covalent binary complex, which subsequently covalently and irreversibly binds to the active GTP-bound form of KRAS G12D (KRASG12D(ON)). This prevents KRAS G12D-mediated signaling and activation of downstream survival pathways. This causes apoptosis in KRAS G12D-expressing tumor cells. In addition, inhibition of KRAS G12D signaling by zoldonrasib abrogates the suppressive tumor microenvironment (TME) and enhances an anti-tumor immune response which further leads to an inhibition of proliferation of KRAS G12D-expressing tumor cells. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell proliferation, invasion, and metastasis. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| 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 | 0.8558 mL | 4.2792 mL | 8.5584 mL | |
| 5 mM | 0.1712 mL | 0.8558 mL | 1.7117 mL | |
| 10 mM | 0.0856 mL | 0.4279 mL | 0.8558 mL |