It notes that pipobroman has similarities to alkylating agents and mediates its effects by inhibiting DNA and RNA polymerase or by reducing pyrimidine nucleotide incorporation into DNA. [1]

In normal human epidermal keratinocytes (NHEK) treated with pipobroman (10 μM) and vemurafenib (3 μM) for 2 weeks, co-immunoprecipitation analysis showed BRAF-CRAF dimerization and downstream ERK activation (phosphorylated ERK) in treated cells, which was not observed in untreated controls. Epidermal growth factor receptor (EGFR) was not activated in treated keratinocytes, suggesting that on pipobroman treatment, keratinocytes acquire genetic alterations leading to RAS activation independently of EGFR. [2]

In a randomized clinical trial (French Polycythemia Study Group/French Intergroup of Myeloproliferative Neoplasms) in patients with polycythemia vera (PV) younger than 65 years, pipobroman was administered as first-line therapy. In the intention-to-treat population (n = 149), the median overall survival was 15.4 years (95% CI, 13.4 to 17.0 years), compared to 20.3 years in the hydroxyurea arm (P = 0.008). [1]
The cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) in the pipobroman arm was 13.1%, 34.1%, and 52.1% at 10, 15, and 20 years, respectively, compared to 6.6%, 16.5%, and 24.2% in the hydroxyurea arm (P = 0.004). In patients who received only pipobroman during follow-up (n = 130), the cumulative incidence of AML/MDS was 14.6%, 34%, and 49.4% at 10, 15, and 20 years, respectively (P = 0.002 vs. hydroxyurea alone). [1]
The cumulative incidence of myelofibrosis (MF) in the intention-to-treat pipobroman arm was 7.8%, 15.7%, and 27% at 10, 15, and 20 years, respectively, which was not significantly different from the hydroxyurea arm (P = 0.07). However, in patients who received only pipobroman, the incidence of MF was 5.1%, 9.8%, and 21.3% at 10, 15, and 20 years, respectively. [1]
Vascular event incidence was not significantly different between the pipobroman and hydroxyurea arms (P = 0.61 in intention-to-treat analysis), indicating both drugs were equally active in reducing thrombotic complications. [1]
The median treatment duration for pipobroman was 9.5 years, compared to 12 years for hydroxyurea (P < 0.001). [1]
In patients randomly assigned to hydroxyurea, switching to pipobroman during follow-up significantly increased the risk of death (hazard ratio, 2.06; 95% CI, 1.09 to 3.87; P = 0.026). In patients randomly assigned to pipobroman, switching to hydroxyurea did not modify the risk of death (hazard ratio, 1.37; 95% CI, 0.61 to 3.08; P = 0.45). [1]

Proximity ligation assay (Duolink): Following dewaxing and rehydration of tissue sections, antigen retrieval was performed by heating slides for 30 minutes at 95°C in Tris-EDTA buffer (pH 9). Primary antibodies (BRAF, mouse, clone F7, 1:50; CRAF, rabbit, clone C12, 1:50) were incubated overnight at 4°C. PLA minus and PLA plus probes (containing secondary antibodies conjugated to oligonucleotides) were added and incubated for 1 hour at 37°C. Oligonucleotides were then added and allowed to hybridize to the PLA probes. Ligase was used to join the two hybridized oligonucleotides into a closed circle. DNA was amplified by rolling circle amplification, and detection was carried out using an orange detection kit. Cell nuclei were stained with DAPI. Fluorescence microscopy was used to visualize results, and the number of PLA signals per cell was counted using Duolink Image Tool. [2]

Normal human epidermal keratinocytes (NHEK) were treated with DMSO (control) or with pipobroman (10 μM) and vemurafenib (3 μM). After 2 weeks of treatment, cells were lysed in RIPA buffer. CRAF was immunoprecipitated and probed for BRAF. Lysates were also probed for pEGFR (Y1068), BRAF, CRAF, phosphorylated ERK (ppERK), and total ERK. [2]

Absorption, Distribution and Excretion
This drug is well absorbed through the gastrointestinal tract. After oral administration, the drug is well absorbed. No studies have been reported regarding its distribution and metabolism in the human body.

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Pipobroman is associated with a significant risk of leukemic transformation (AML/MDS). In this long-term randomized trial, the cumulative incidence of AML/MDS at 15 years was 34.1% in the intention-to-treat population and 37.5% in patients whose main treatment was pipobroman. The increased risk was not dependent on treatment duration (Grambsch and Therneau proportional hazard test P = 0.75). [1]
The study concludes that pipobroman is leukemogenic and unsuitable for first-line therapy in polycythemia vera. [1]

[1]. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol. 2011 Oct 10;29(29):3907-13.

[2]. Association of Vemurafenib and Pipobroman Enhances BRAF-CRAF Dimerization in Squamous Cell Carcinoma. J Invest Dermatol. 2016 Jun;136(6):1302-1305.

Piperobromane may have developmental toxicity depending on state or federal labeling requirements. Piperobromane is an N-acylpiperazine with the structure piperazine, each nitrogen atom acylated by 3-bromopropionyl. It is an anticancer drug with antitumor and alkylating effects. It is an N-acylpiperazine, tertiary amide, and organobromine compound. It is a drug that exerts its antitumor effect through alkylation. There are reports of piperbromane's presence in bovine (Bos taurus), and relevant data exist. Piperobromane is a piperazine derivative with potential antitumor alkylating activity. Although the exact mechanism of action of piperbromane is not fully elucidated, the drug appears to work by alkylating DNA, leading to interruption of DNA replication and ultimately cell death. A drug that exerts its antitumor effect through alkylation.
Drug Indications
For the treatment of polycythemia vera and refractory chronic myeloid leukemia.

Indications
For the treatment of polycythemia vera and refractory chronic myeloid leukemia.
Mechanism of Action Its mechanism of action is not yet fully understood, but due to its structural similarity to other DNA alkylating agents, piperobromidine is thought to disrupt DNA synthesis through alkylation, ultimately leading to cell death. Piperobromidine has been classified as a multifunctional alkylating agent, but its exact mechanism of action remains unclear. Therapeutic Uses Antitumor drug, alkylating agent… Alkylated antitumor drug. Currently, piperobromidine is primarily used to treat polycythemia vera and chronic myeloid leukemia. Even in these diseases, the efficacy of piperobromidine is often less than that of previous treatments. For leukemia patients, piperobromidine is only used in patients unresponsive to X-rays and busulfan; for polycythemia vera patients, piperobromidine is only used in patients unresponsive to phlebotomy and radiophosphate therapy. Piperobromidine is primarily used to treat polycythemia vera. In the limited published studies, there appears to be no difference in treatment response between patients who have previously received other drug treatments and those who have not. Currently, there is insufficient data to compare the efficacy of piperobromandibular joint with conventional treatments (radioactive phosphorus, phlebotomy, or other alkylating agents); however, piperobromandibular joint may be effective in patients with polycythemia vera who have not responded to these therapies. Although piperobromandibular joint has achieved remission in chronic myeloid leukemia, the number of reported cases is too small to assess the efficacy of this drug in this disease; therefore, the use of piperobromandibular joint is limited to patients who have not responded to other therapies. Drug Warnings Patients with persistent bone marrow suppression due to prior radiotherapy or other cytotoxic chemotherapy should not receive piperobromandibular joint. There is insufficient clinical experience to support the use of this drug in children under 15 years of age. Due to a lack of information on its potential teratogenicity, piperobromandibular joint is contraindicated in pregnant women. Skin rash and gastrointestinal adverse reactions such as nausea, vomiting, abdominal cramps, diarrhea, and anorexia may occur. These adverse reactions are usually transient but may persist and require discontinuation of treatment. Piperobromandibular joint is contraindicated in patients with bone marrow suppression due to radiotherapy or cytotoxic chemotherapy.

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Pharmacodynamics
Pipobroman is an antitumor drug. Specifically, it is a piperazine derivative with a chemical structure similar to many DNA alkylating agents. Pipobroman has proven clinical efficacy against polycythemia vera and essential thrombocythemia.

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Pipobroman is a bromide derivative of piperazine that has similarities to alkylating agents. It exerts its effects by inhibiting DNA and RNA polymerase or by reducing pyrimidine nucleotide incorporation into DNA. It has been used extensively in Europe, particularly in France and Italy, for the treatment of polycythemia vera. Early research in the United States showed pipobroman to be an effective agent in PV. This randomized trial (FPSG/FIM) comparing pipobroman with hydroxyurea as first-line therapy in patients with PV younger than 65 years found that pipobroman is associated with significantly higher rates of transformation to AML/MDS and shorter overall survival compared to hydroxyurea, while both drugs were equally effective in reducing vascular events. Based on these results, pipobroman is considered unsuitable for first-line therapy in PV. [1]

C10H16BR2N2O2

356.05

353.958

C, 33.73; H, 4.53; Br, 44.88; N, 7.87; O, 8.99

54-91-1

4842

White to off-white solid powder

1.691g/cm3

487.1ºC at 760mmHg

106-107ºC

248.4ºC

1.566

1.103

0

2

4

16

227

0

O=C(N1CCN(C(CCBr)=O)CC1)CCBr

NJBFOOCLYDNZJN-UHFFFAOYSA-N

InChI=1S/C10H16Br2N2O2/c11-3-1-9(15)13-5-7-14(8-6-13)10(16)2-4-12/h1-8H2

3-bromo-1-[4-(3-bromopropanoyl)piperazin-1-yl]propan-1-one

Pipobroman; NSC25154; Trade names Vercite Vercyte

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: ~71 mg/mL (~199.4 mM)
Ethanol: ~71 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.84 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.84 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.

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