PM01183 is a newly developed synthetic alkaloid tetrahydroisoquinoline that is used to treat solid tumors. PM01183: Double-strand breaks in living cells are caused by DNA adducts, which lead to the accumulation of S-phase and subsequent cell disinfection. With an average GI50 value of 2.7 nM, PM01183's strong cytotoxic activity was found in a panel of 23 cell lines [2]. In vitro, lurbinectedin significantly inhibits human ovarian clear cell carcinoma (CCC) cells that are both chemically sensitive and robust[1].

Lurbinectedin effectively suppressed tumor growth in CCC cell xenografts. There is a notable synergistic effect between SN-38 and luerbinectedin [1]. PM01183 markedly suppressed tumor growth in a four-cell xenograft model of human cancer, while lurbinectedin or NSC 119875 combination therapy effectively cured NSC 119875-sensitive and NSC 119875-combined single preclinical ovarian carcinoma tumors in animals. The combined treatment showed the greatest positive results, particularly for NSC 119875. inside tumors. Reduced proliferation, increased aberrant mitotic rates in malignancies, and triggered apoptosis are linked to luerbinectedin growth inhibition [3].

Absorption, Distribution and Excretion
Following intravenous administration, the Cmax and AUC0-inf were 107 µg/L and 551 µg*h/L, respectively. No accumulation between dosing intervals (every 3 weeks) has been observed. No significant differences in absorption were found between special populations (e.g. based on age, sex, ethnicity, etc.), but lurbinectedin has not been studied in the setting of severe renal impairment or moderate/severe hepatic impairment.
Approximately 89% of a given dose is recovered in the feces (<0.2% unchanged) and 6% in the urine (1% unchanged).
The steady-state volume of distribution of lurbinectedin is 504 L.
The total plasma clearance of lurbinectedin is approximately 11 L/h.

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Metabolism / Metabolites
Lurbinectedin is metabolized primarily by CYP3A4 _in vitro_, though specific data regarding its biotransformation are lacking. An N-desmethylated metabolite has been identified in canine subjects.

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Biological Half-Life
The terminal half-life of lurbinectedin is 51 hours.

Hepatotoxicity
Elevations in serum aminotransferase levels arise in approximately two-thirds of patients treated with lurbinectedin and elevations above 5 times the upper limit of normal occur in 4% to 5% of patients. Pretreatment with dexamethasone appears to decrease the degree and frequency of enzyme elevations. The elevations arise within 2 to 5 days of the intravenous infusion, rise to maximal levels between 5 and 9 days, and generally fall to baseline values within 2 to 3 weeks. Minor elevations in serum alkaline phosphatase and bilirubin are also common. However, clinically apparent liver injury with jaundice from lurbinectedin is uncommon. On the other hand, patients with underlying liver disease appear to be at increased risk for septicemia and multiorgan failure as a result of chemotherapy, and monitoring of liver tests before and during lurbinectedin therapy is recommended. The severe liver injury typically mimics acute decompensation of an underlying cirrhosis with modest elevations in serum enzymes and worsening jaundice and hepatic synthetic dysfunction. Immunoallergic and autoimmune features are uncommon. Fatalities are generally due to sepsis and multiorgan failure rather than typical acute liver failure.
Likelihood score: D (possible cause of clinically apparent liver injury, generally in the setting of preexisting liver disease and use of high doses).

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Protein Binding
Lurbinectedin is highly protein-bound in plasma (~99%) to both serum albumin and α-1-acid glycoprotein.

[1]. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary. PLoS One. 2016 Mar 17;11(3):e0151050.

[2]. PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol. 2010 Nov;161(5):1099-110.

[3]. Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of NSC 119875-resistant epithelial ovarian cancer. Clin Cancer Res. 2012 Oct 1;18(19):5399-411.

Lurbinectedin is a DNA alkylating agent that has been investigated in the treatment of a variety of cancers, including mesothelioma, chronic lymphocytic leukemia (CLL), breast cancer, and small-cell lung cancer (SCLC). It is a derivative of the marine-derived agent ecteinascidin ([trabectedin]), an anticancer agent found in extracts of the tunicate Ecteinascidia turbinata, with the primary difference being the substitution of the tetrahydroisoquinoline with a tetrahydro β‐carboline that results in increased antitumour activity of lurbinectedin as compared to its predecessor. On June 15, 2020, the FDA granted accelerated approval and orphan drug designation to lurbinectedin for the treatment of adult patients with metastatic SCLC who have experienced disease progression despite therapy with platinum-based agents. This accelerated approval is based on the rate and duration of therapeutic response observed in ongoing clinical trials and is contingent on the verification of these results in confirmatory trials.
Lurbinectedin is an Alkylating Drug. The mechanism of action of lurbinectedin is as an Alkylating Activity.
Lurbinectedin is an antineoplastic alkylating agent and synthetic derivative of trabectedin that is used to treat refractory, metastatic small cell lung cancer. Lurbinectedin therapy is associated with a high rate of transient serum enzyme elevations during treatment and with occasional instances of clinically apparent liver injury with jaundice.
Lurbinectedin is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity. Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.

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Drug Indication
Lurbinectedin is indicated for the treatment of adult patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.
Treatment of malignant mesothelioma
Treatment of small cell lung cancer

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Mechanism of Action
Lurbinectedin is a DNA alkylating agent. It covalently binds to guanine residues in the DNA minor groove, forming adducts that bend the DNA helix towards the major groove. This process triggers a cascade of events that affect the activity of transcription factors and impairs DNA repair pathways, ultimately leading to double-strand DNA breaks and eventual cell death. Additional mechanism(s) of action include inhibition of RNA-polymerase-II activity, inactivation of Ewing Sarcoma Oncoprotein (EWS-FL11) via nuclear redistribution, and the inhibition of human monocyte activity and macrophage infiltration into tumor tissue.

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Pharmacodynamics
Lurbinectedin exerts its chemotherapeutic activity by covalently binding to DNA, resulting in double-strand DNA breaks and subsequent cell death. Lurbinectedin has been associated with myelosuppression, and patients receiving therapy with this agent should be closely monitored for evidence of cytopenias. Prior to beginning therapy, ensure baseline neutrophil counts are >1,500 cells/mm³ and platelet counts are >100,000/mm³. The supplementary use of granulocyte colony-stimulating factor (G-CSF) should be considered if the neutrophil count falls below 500 cells/mm³. Lurbinectedin has also been associated with hepatotoxicity. Monitor liver function tests at baseline and regular intervals throughout therapy, and consider holding, reducing, or permanently discontinuing therapy based on the severity of observed hepatotoxicity.

C41H44N4O10S

784.88

784.278

C, 62.74; H, 5.65; N, 7.14; O, 20.38; S, 4.08

497871-47-3

Lurbinectedin-d3

57327016

White to light yellow solid powder

4.393

4

14

4

56

1530

7

S1C[C@@]2(C3=C(C4C=C(C=CC=4N3)OC)CCN2)C(=O)OC[C@@]2([H])C3=C4C(=C(C)C(=C3[C@]1([H])[C@@]1([H])[C@@]3([H])C5C(=C(C(C)=CC=5C[C@@]([H])([C@@H](N12)O)N3C)OC)O)OC(C)=O)OCO4

YDDMIZRDDREKEP-HWTBNCOESA-N

InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1

[(1R,2R,3R,11S,12S,14R,26R)-5,12-dihydroxy-6,6'-dimethoxy-7,21,30-trimethyl-27-oxospiro[17,19,28-trioxa-24-thia-13,30-diazaheptacyclo[12.9.6.13,11.02,13.04,9.015,23.016,20]triaconta-4(9),5,7,15,20,22-hexaene-26,1'-2,3,4,9-tetrahydropyrido[3,4-b]indole]-22-yl] acetate

PM-01183 PM01183 Lurbinectedin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~20 mg/mL (~25.48 mM)

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.

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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).

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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)

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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).

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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

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)