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MedKoo Cat#: 207170 | Name: MRTX1133
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

MRTX1133 is a potent and selective KRAS G12D inhibitor. MRTX1133 targets the KRAS G12D protein in both active and inactive states. In preclinical studies, MRTX1133 exhibited a long half-life, an ability to bind the KRAS G12D protein in both active and inactive states, and selective inhibition of KRAS G12D mutant cancer cells. In G12D mutant tumor models, MRTX1133 showed dose-dependent selective inhibition of the KRAS pathway and tumor regression.

Chemical Structure

MRTX1133
MRTX1133
CAS#2621928-55-8

Theoretical Analysis

MedKoo Cat#: 207170

Name: MRTX1133

CAS#: 2621928-55-8

Chemical Formula: C33H31F3N6O2

Exact Mass: 600.2461

Molecular Weight: 600.65

Elemental Analysis: C, 65.99; H, 5.20; F, 9.49; N, 13.99; O, 5.33

Price and Availability

Size Price Availability Quantity
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,650.00 Ready to Ship
1g USD 3,450.00 Ready to ship
2g USD 5,850.00 Ready to ship
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Related CAS #
2621928-55-8
Synonym
MRTX1133; MRTX-1133; MRTX 1133;
IUPAC/Chemical Name
2-Naphthalenol, 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-[[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-
InChi Key
SCLLZBIBSFTLIN-IFMUVJFISA-N
InChi Code
InChI=1S/C33H31F3N6O2/c1-2-23-26(35)7-4-18-10-22(43)11-24(27(18)23)29-28(36)30-25(13-37-29)31(41-15-20-5-6-21(16-41)38-20)40-32(39-30)44-17-33-8-3-9-42(33)14-19(34)12-33/h1,4,7,10-11,13,19-21,38,43H,3,5-6,8-9,12,14-17H2/t19-,20?,21?,33+/m1/s1
SMILES Code
OC1=CC(C2=C(F)C3=NC(OC[C@@]45CCCN4C[C@H](F)C5)=NC(N6CC(N7)CCC7C6)=C3C=N2)=C8C(C#C)=C(F)C=CC8=C1
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
To be determined
Shelf Life
>2 years if stored properly
Drug Formulation
To be determined
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein.
Biological target:
MRTX1133 inhibits ERK phosphorylation in the AGS cell line with an IC50 ranging 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, the IC50 of MRTX1133 is 6 nM against AGS cells (KRAS G12D), while demonstrating more than 500-fold selectivity against MKN1, a cell line which is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS.
In vitro activity:
MRTX-1133 also completely inhibited ERK phosphorylation in Mia PaCa-2 and SW620 cells, harboring KRAS G12C or G12V mutations, respectively (Fig. 5B and D). This can be observed clearly when the profiling data is presented for each compound separately and compared using the 4 cell lines (Fig. 6). Fig. 6.E showed that MRTX-1133 can inhibit KRAS G12C and G12V, albeit with a higher IC50 than its main target of KRAS G12D. This demonstrates MRTX-1133 is very selective towards KRAS G12D versus wild type KRAS and indicates that targeting KRAS G12V could be possible. Reference: SLAS Discov. 2022 Jun;27(4):249-257. https://pubmed.ncbi.nlm.nih.gov/35288294/
In vivo activity:
Intraperitoneal (IP) administration of MRTX1133 at 30 mg/kg in CD-1 mice (Figure 12) resulted in sustained plasma exposure exceeding the free-fraction-adjusted pERK IC50 value in the KRASG12D mutant Panc 04.03 cell line for approximately 8 h. Encouraged by this result, this study evaluated the ability to modulate KRAS-dependent ERK phosphorylation in the Panc 04.03 xenograft tumor model at 30 mg/kg BID (IP) and observed 62% and 74% inhibition of pERK signal at 1 and 12 h after the second dose, respectively (Figure 13). An antitumor efficacy study in this model resulted in MRTX1133 dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of −62% and −73% observed at 10 and 30 mg/kg BID (IP), respectively (Figure 14). Reference: J Med Chem. 2022 Feb 24;65(4):3123-3133. https://pubmed.ncbi.nlm.nih.gov/34889605/
Solvent mg/mL mM
Solubility
DMSO 50.0 83.24
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 600.65 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257. doi: 10.1016/j.slasd.2022.03.001. Epub 2022 Mar 12. PMID: 35288294. 2. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605.
In vitro protocol:
1. Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257. doi: 10.1016/j.slasd.2022.03.001. Epub 2022 Mar 12. PMID: 35288294. 2. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605.
In vivo protocol:
1. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605.
1: Vázquez-Borrego MC, Granados-Rodríguez M, Bura FI, Martínez-López A, Rufián- Andújar B, Valenzuela-Molina F, Rodríguez-Ortiz L, Haro-Yuste S, Moreno-Serrano A, Ortega-Salas R, Pineda-Reyes R, Michán C, Alhama J, Romero-Ruiz A, Arjona- Sánchez Á. Antitumor effect of a small-molecule inhibitor of KRASG12D in xenograft models of mucinous appendicular neoplasms. Exp Hematol Oncol. 2023 Dec 8;12(1):102. doi: 10.1186/s40164-023-00465-4. PMID: 38066554; PMCID: PMC10704766. 2: Orsburn BC. Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRASG12D Inhibitor MRTX1133. J Proteome Res. 2023 Dec 1;22(12):3703-3713. doi: 10.1021/acs.jproteome.3c00212. Epub 2023 Nov 20. PMID: 37983312; PMCID: PMC10696623. 3: Xiao X, Feng J, Ma J, Xia X, Liu X, Zhang J, Ding C, Pang X, Zhang A. Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3-d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRASG12D Inhibitors. J Med Chem. 2023 Nov 23;66(22):15524-15549. doi: 10.1021/acs.jmedchem.3c01724. Epub 2023 Nov 3. PMID: 37921024. 4: Wei D, Wang L, Zuo X, Maitra A, Bresalier RS. A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer. Clin Cancer Res. 2023 Oct 13. doi: 10.1158/1078-0432.CCR-23-2098. Epub ahead of print. PMID: 37831007. 5: Kataoka M, Kitazawa M, Nakamura S, Koyama M, Yamamoto Y, Miyazaki S, Hondo N, Tanaka H, Soejima Y. Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRASG12D Inhibitor, in Colorectal Cancer Treatment. Anticancer Res. 2023 Oct;43(10):4341-4348. doi: 10.21873/anticanres.16629. PMID: 37772552. 6: Mahadevan KK, McAndrews KM, LeBleu VS, Yang S, Lyu H, Li B, Sockwell AM, Kirtley ML, Morse SJ, Moreno Diaz BA, Kim MP, Feng N, Lopez AM, Guerrero PA, Paradiso F, Sugimoto H, Arian KA, Ying H, Barekatain Y, Sthanam LK, Kelly PJ, Maitra A, Heffernan TP, Kalluri R. KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells. Cancer Cell. 2023 Sep 11;41(9):1606-1620.e8. doi: 10.1016/j.ccell.2023.07.002. Epub 2023 Aug 24. PMID: 37625401. 7: Zeissig MN, Ashwood LM, Kondrashova O, Sutherland KD. Next batter up! Targeting cancers with KRAS-G12D mutations. Trends Cancer. 2023 Nov;9(11):955-967. doi: 10.1016/j.trecan.2023.07.010. Epub 2023 Aug 15. PMID: 37591766. 8: Gulay KCM, Zhang X, Pantazopoulou V, Patel J, Esparza E, Pran Babu DS, Ogawa S, Weitz J, Ng I, Mose ES, Pu M, Engle DD, Lowy AM, Tiriac H. Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2023 Sep 15;83(18):3001-3012. doi: 10.1158/0008-5472.CAN-23-1313. PMID: 37378556; PMCID: PMC10502451. 9: Keats MA, Han JJW, Lee YH, Lee CS, Luo J. A Nonconserved Histidine Residue on KRAS Drives Paralog Selectivity of the KRASG12D Inhibitor MRTX1133. Cancer Res. 2023 Sep 1;83(17):2816-2823. doi: 10.1158/0008-5472.CAN-23-0592. PMID: 37339170; PMCID: PMC10528543. 10: Khan S, Budamagunta V, Zhou D. Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. Adv Cancer Res. 2023;159:145-184. doi: 10.1016/bs.acr.2023.02.004. Epub 2023 Mar 9. PMID: 37268395. 11: Kumarasamy V, Frangou C, Wang J, Wan Y, Dynka A, Rosenheck H, Dey P, Abel EV, Knudsen ES, Witkiewicz AK. Pharmacologically targeting KRAS G12D in PDAC models: tumor cell intrinsic and extrinsic impact. bioRxiv [Preprint]. 2023 Apr 20:2023.03.18.533261. doi: 10.1101/2023.03.18.533261. PMID: 37162905; PMCID: PMC10168422. 12: Zhou X, Ji Y, Zhou J. Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors. Molecules. 2023 Apr 21;28(8):3615. doi: 10.3390/molecules28083615. PMID: 37110848; PMCID: PMC10146153. 13: Feng J, Hu Z, Xia X, Liu X, Lian Z, Wang H, Wang L, Wang C, Zhang X, Pang X. Feedback activation of EGFR/wild-type RAS signaling axis limits KRASG12D inhibitor efficacy in KRASG12D-mutated colorectal cancer. Oncogene. 2023 May;42(20):1620-1633. doi: 10.1038/s41388-023-02676-9. Epub 2023 Apr 5. PMID: 37020035; PMCID: PMC10181928. 14: Orsburn BC. Metabolomic, proteomic and single cell proteomic analysis of cancer cells treated with the KRASG12D inhibitor MRTX1133. bioRxiv [Preprint]. 2023 Sep 13:2023.03.23.533981. doi: 10.1101/2023.03.23.533981. Update in: J Proteome Res. 2023 Dec 1;22(12):3703-3713. PMID: 36993160; PMCID: PMC10055375. 15: Liang F, Kang Z, Sun X, Chen J, Duan X, He H, Cheng J. Inhibition mechanism of MRTX1133 on KRASG12D: a molecular dynamics simulation and Markov state model study. J Comput Aided Mol Des. 2023 Mar;37(3):157-166. doi: 10.1007/s10822-023-00498-1. Epub 2023 Feb 28. PMID: 36849761. 16: Ji X, Li Y, Kong X, Chen D, Lu J. Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRASG12D Mutation. ACS Omega. 2023 Feb 9;8(7):7211-7221. doi: 10.1021/acsomega.3c00329. PMID: 36844555; PMCID: PMC9948199. 17: Mahadevan KK, McAndrews KM, LeBleu VS, Yang S, Lyu H, Li B, Sockwell AM, Kirtley ML, Morse SJ, Moreno Diaz BA, Kim MP, Feng N, Lopez AM, Guerrero PA, Sugimoto H, Arian KA, Ying H, Barekatain Y, Kelly PJ, Maitra A, Heffernan TP, Kalluri R. Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner. bioRxiv [Preprint]. 2023 Feb 18:2023.02.15.528757. doi: 10.1101/2023.02.15.528757. PMID: 36824971; PMCID: PMC9948969. 18: Mainardi S. With a little help from my T friends: T cells increase efficacy of KRAS (G12D) inhibitors. Cell Rep Med. 2023 Feb 21;4(2):100950. doi: 10.1016/j.xcrm.2023.100950. PMID: 36812887; PMCID: PMC9975326. 19: Larson JE, Hardy PB, Schomburg NK, Wang X, Kireev D, Rossman KL, Pearce KH. Development of a high-throughput TR-FRET screening assay for a fast-cycling KRAS mutant. SLAS Discov. 2023 Jan;28(1):39-47. doi: 10.1016/j.slasd.2022.12.001. Epub 2022 Dec 21. PMID: 36563789. 20: Bannoura SF, Khan HY, Azmi AS. KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered? Front Oncol. 2022 Nov 29;12:1013902. doi: 10.3389/fonc.2022.1013902. PMID: 36531078; PMCID: PMC9749787.