Lecirelin acetate is an artificially synthesized octapeptide analogue of somatostatin, belonging to the class of somatostatin receptor ligands (SRLs). Its chemical formula is C59H84N16O12, molecular weight is 1096.34, and CAS registration number is 108736-35-2. The drug was developed by Ipsen Pharma Biotech Sas in France, and its trade name is Somatuline Depot. It was first approved for market in the European Union in February 2005, approved by the US FDA in August 2007, and approved for the treatment of acromegaly in China in December 2007.
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Lecirelin COA
Lecirelin acetate is currently the first successfully developed sustained-release formulation of somatostatin, and is a novel long-acting somatostatin (SM) octapeptide analogue. It is a peptide inhibitor for many endocrine, neuroendocrine, exocrine, and paracrine functions. Studies have shown that it may primarily exert its effects by binding to somatostatin receptors (SMRs), with good affinity for peripheral (pituitary and pancreatic) SMRs and weaker affinity for central receptors.
1. Prostate cancer
It is gradually emerging in the field of prostate cancer treatment, and its potential therapeutic value is constantly being explored and recognized.
Bone metastasis pain:
Prostate cancer patients often experience bone metastasis, and the pain caused by bone metastasis seriously affects the patient's quality of life and daily activity ability. The combination of bisphosphonates provides an effective treatment option for relieving bone metastasis pain. Bisphosphonates can inhibit the activity of osteoclasts, reduce bone resorption, enhance bone strength, and prevent the occurrence of bone related events (SREs) such as fractures. Besides having direct anti-tumor effects, acetic acid lanrelitid may also improve the microenvironment of bone metastasis sites by regulating the expression of bone metabolism related factors. The combination of the two can produce a synergistic effect, significantly enhancing the relief of bone pain, reducing the frequency of bone related events, and alleviating the pain of patients.
2. breast cancer
The exploration in the treatment of breast cancer has also made some progress, providing more treatment options for breast cancer patients.
Bone metastasis management:
Breast cancer patients are also prone to bone metastasis, which can lead to serious complications such as bone pain and fracture, and seriously affect the quality of life of patients. Combination with anti bone resorption drugs is an effective strategy to manage bone metastasis of breast cancer. Anti bone resorption drugs such as zoledronic acid can inhibit the activity of osteoclasts, reduce bone resorption, and enhance bone strength. In addition to its anti-tumor effect, it may also regulate bone metabolism balance, promote bone formation, synergize with anti bone resorption drugs, better alleviate bone pain, prevent fractures, and improve patients' self-care ability.
Potential of Combination Therapy: Synergistic Enhancement Strategy
The combination with other drugs can significantly enhance therapeutic efficacy, expand treatment indications, and bring new breakthroughs to the treatment of various diseases.
Combined with targeted drugs
For example, the combination of lanrelitide acetate and everolimus has achieved remarkable results in the treatment of advanced gastrointestinal pancreatic neuroendocrine tumors (GEP NETs). Everolimus is a mammalian inhibitor of the target protein of rapamycin (mTOR), which can inhibit the growth and proliferation of tumor cells. By inhibiting the secretion of growth factors such as growth hormone and insulin-like growth factor-1 (IGF-1), the growth environment of tumor cells is regulated. The combination of the two can produce a synergistic effect, inhibiting the growth and metastasis of tumor cells from multiple aspects. The ELECT study results show that this combination therapy can significantly prolong the progression free survival (PFS) of patients to 16.5 months, providing a more effective treatment option for advanced GEP NETs patients.
Combined with chemotherapy
Chemotherapy is one of the commonly used treatment methods in the treatment of non-small cell lung cancer, but chemotherapy drugs often cause a series of adverse reactions, such as nausea, vomiting, and mucosal inflammation, which seriously affect the patient's quality of life and treatment compliance. Combined use with chemotherapy drugs can have unique advantages. It can protect the gastrointestinal mucosa, reduce the damage of chemotherapy drugs to the gastrointestinal mucosa, thereby reducing the incidence and severity of chemotherapy-induced nausea, vomiting, and mucosal inflammation. This enables patients to better tolerate chemotherapy, ensuring the smooth progress of chemotherapy and improving treatment efficacy.
Combined with immunotherapy
Immunotherapy is a major breakthrough in the field of tumor treatment in recent years. Immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors can activate the body's immune system and enhance the killing effect of immune cells on tumor cells. The combination with immunotherapy drugs may further enhance the efficacy of PD-1/PD-L1 inhibitors by regulating the immune cell function in the tumor microenvironment. There are various immune suppressive cells and factors in the tumor microenvironment that inhibit the activity and function of immune cells, allowing tumor cells to evade immune surveillance. It is possible to improve the immune status of the tumor microenvironment, promote immune cell recognition and killing of tumor cells, and enhance the effectiveness of immunotherapy by regulating the expression of these immunosuppressive cells and factors.
Research and development and discovery background
Research and development background: Reproductive regulation mechanism based on GnRH
It is a synthetic gonadotropin-releasing hormone (GnRH) analog. GnRH is a peptide hormone secreted by the hypothalamus, which regulates gonadal development and reproductive cycle by stimulating the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. In the field of animal reproduction, the development of GnRH analogs aims to address the following issues:
Ovarian dysfunction:
Such as bovine ovarian follicular cysts, leading to ovulation disorders and decreased reproductive rates.
Synchronization of reproductive cycles:
Improve the efficiency of artificial insemination and optimize livestock production.
Limitations of hormone therapy:
Natural GnRH has a short half-life and requires frequent injections, while synthetic analogues can prolong the duration of action through structural modifications.
Discovery Process: Optimization from Natural GnRH to Lecirelin
Identification of Natural GnRH:
In 1971, Schally and Guillemin's team first isolated GnRH from the hypothalamus of pigs and determined its decapeptide structure (pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2). This discovery laid the foundation for the study of synthetic analogues.
Structural modification and activity optimization:
By replacing or modifying the amino acid residues of natural GnRH, scientists have developed various analogues aimed at:
Its amino acid sequence is H-Pyr-His-Trp-Ser-Tyr-D-Gly (tBu) - Leu-Arg-Pro-NHEt, where:
D-Gly (tBu):
The tertiary butyl modification of D-type glycine enhances its resistance to enzymatic hydrolysis.
Pro NHEt:
The ethylation modification of proline prolongs the action time.
Animal experiment verification:
Research has shown that n can significantly increase the contraction frequency of bovine preovulatory follicles, promote follicle maturation and ovulation. For example, in hybrid cows, injection on the 7th day after artificial insemination can increase pregnancy rates and regulate serum progesterone levels.
R&D milestone: from laboratory to clinical application
The research and development of synthetic GnRH analogs (such as Buserelin and Triptorelin) have verified the effect of structural modifications on activity, and preliminary synthesis and in vitro activity screening have been conducted.
Approved for the treatment of bovine ovarian follicular cysts, it has become an important reproductive management tool in animal husbandry.
The research extends to other animals such as horses and pigs to explore their applications in inducing ovulation and synchronizing estrus.
Although mainly applied in veterinary medicine, its structural optimization strategy has inspired the development of human GnRH analogs (such as Degarelix, used for prostate cancer treatment).
Preparation method:
After removing the Fmoc protecting group on the Rink amide resin, the first amino acid Fmoc Thr (tBu) is loaded onto the resin through conventional coupling. Wash the resin, remove the Fmoc protecting group, and introduce the second amino acid Fmoc Cys (Acm) to initiate the second coupling. First, activate the amino acids protected by Fmoc using TBTU/HOBt, and then perform coupling using diisopropylethylamine or methyl pyridine as organic bases (indicated by the indene ketone experiment to determine if coupling is complete). Wash the resin and remove the Fmoc groups on the a-amine using a DMF solution containing 20% piperidine by volume (p). According to the peptide sequence, repeat the above steps with different amino acids each time [all amino acids used are protected with Fmoc-N; Tyr(tBu), Lys(Boc), Thr(tBu), Cys(Trt). Wash the resin with DMF and then vacuum dry it with DCM. Wash with a solvent containing 95% (p) TFA, 2.5% (p) TIS, and 2.5% (p) EDT to remove acid sensitive protective groups and separate the peptide from the resin. Add ether to precipitate the product, filter, and vacuum dry. Purification using C18 reverse phase high-performance liquid chromatography column. Add an equal amount of iodoacetic acid solution with strong stirring at room temperature (neutralize excess iodine with a small amount of ascorbic acid). The obtained solution was purified using a C18 reverse phase high-performance liquid chromatography column to obtain lanrui peptide. Replace the equilibrium ions in the fraction with acetate, collect the fraction, sublime, dry, and obtain lanaritide acetate.
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