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On March 3, 2021, German Merck (Merck KGaA) announced that it has reached a global license agreement with Debiopharm to develop a highly effective oral antagonist of apoptosis protein (IAP) xevinapant (Debio1143), with a transaction amount of up to 898 million euros.
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At the same time, APG-1387, another IAP antagonist with the same target, developed by Yasheng Pharmaceuticals, is currently in the process of clinical development.
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What is IAP? What is IAP?
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Inhibitor of apoptosis proteins (IAPs) are a type of intracellular apoptosis inhibitory proteins, which are widely found in yeast, invertebrates and vertebrates.
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In recent years, researchers have discovered IAP disorders in a variety of tumors, and the high expression of IAP protein promotes tumorigenesis and tumor metastasis, involving lung cancer, head and neck tumors, breast cancer, gastrointestinal tumors, etc.
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Xevinapant is a potential "first-in-class" oral IAP antagonist, which can make tumor cells more sensitive to chemoradiation therapy (CRT) by promoting cell apoptosis and improving anti-tumor immune response.
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At the end of February 2020, based on the results of xevinapant's phase 2 clinical trial, it obtained the FDA-approved breakthrough therapy designation for squamous cell carcinoma of the head and neck.
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The positive long-term efficacy of Xevinapant in Phase 2 clinical studies indicates that IAP antagonists may become a revolutionary method for the treatment of head and neck cancer.
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75em;box-sizing:border-box ;'> So far, no drugs have been approved for IAP protein targets in the global field.
In addition to xevinapant, IAP small molecule inhibitors that have entered the clinical research phase include GDC-0152, LCL161, Birinapant (TL32711) and the APG-1387 mentioned at the beginning.
In addition to xevinapant, IAP small molecule inhibitors that have entered the clinical research phase include GDC-0152, LCL161, Birinapant (TL32711) and the APG-1387 mentioned at the beginning.
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75em;box-sizing:border-box ;'> GDC-0152
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75em;box-sizing:border-box ;'> GDC-0152 is the first IAP monomer inhibitor developed by Genentech to enter clinical trials, and its IC50 for XIAP-BIR3, ML-IAP-BIR3, cIAP1-BIR3 and cIAP2-BIR3 are 28, 14, and 14, respectively.
17 and 43 nmol?L-1, low affinity for cIAP1-BIR2 and cIAP2-BIR2.
In the in vivo study, the researchers administered GDC-0152 orally to mice bearing human breast cancer tumors, once a week, and each time the dose was 10 mg·kg-1 or more according to body weight.
The results of the experiment It was found that the tumor shrank significantly and the mice tolerated the drug well.
The researchers tracked and studied the concentration of GDC-0152 in the blood of mice, dogs, and monkeys to simulate the rapid absorption and metabolism of the drug in the human body.
In a phase I clinical study (NCT00977067) investigating the safety of drugs, 36 subjects with various types of cancer received intravenous infusion of this product at a dose of 0.
049~1.
48 mg·kg-1, daily 1 time for 14 consecutive days.
The pharmacokinetic results showed a linear relationship between drug concentration and dose.
The experimental results are completely consistent with the researchers' expectations, which provide an important reference for further clinical studies of this product.
17 and 43 nmol?L-1, low affinity for cIAP1-BIR2 and cIAP2-BIR2.
In the in vivo study, the researchers administered GDC-0152 orally to mice bearing human breast cancer tumors, once a week, and each time the dose was 10 mg·kg-1 or more according to body weight.
The results of the experiment It was found that the tumor shrank significantly and the mice tolerated the drug well.
The researchers tracked and studied the concentration of GDC-0152 in the blood of mice, dogs, and monkeys to simulate the rapid absorption and metabolism of the drug in the human body.
In a phase I clinical study (NCT00977067) investigating the safety of drugs, 36 subjects with various types of cancer received intravenous infusion of this product at a dose of 0.
049~1.
48 mg·kg-1, daily 1 time for 14 consecutive days.
The pharmacokinetic results showed a linear relationship between drug concentration and dose.
The experimental results are completely consistent with the researchers' expectations, which provide an important reference for further clinical studies of this product.
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75em;box-sizing:border-box ;'> LCL161
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75em;box-sizing:border-box ;'> LCL161 is an IAP monomer inhibitor developed by Novartis, which mainly acts on XIAP, cIAP1 and cIAP2.
In a phase I clinical trial (NCT01098838) participated by patients with solid tumors, 53 test patients received LCL-161 oral treatment (10~3 000 mg · m-2, medication for 1 day, drug withdrawal for 6 days).
21 days is a course of treatment.
The study results show that the maximum tolerated dose (MTD) of LCL-161 is 1 800 mg · m-2, and 3 patients (6%) developed cytokine release syndrome (CRS), which is the only The emergence of dose-limiting toxicity (DLT).
In addition, there are some common but not serious adverse reactions (nausea, vomiting, fatigue and anorexia).
Currently, a number of clinical studies of LCL161 are in progress.
In a phase I clinical trial (NCT01098838) participated by patients with solid tumors, 53 test patients received LCL-161 oral treatment (10~3 000 mg · m-2, medication for 1 day, drug withdrawal for 6 days).
21 days is a course of treatment.
The study results show that the maximum tolerated dose (MTD) of LCL-161 is 1 800 mg · m-2, and 3 patients (6%) developed cytokine release syndrome (CRS), which is the only The emergence of dose-limiting toxicity (DLT).
In addition, there are some common but not serious adverse reactions (nausea, vomiting, fatigue and anorexia).
Currently, a number of clinical studies of LCL161 are in progress.
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75em;box-sizing:border-box ;'> Birinapant (TL32711)
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75em;box-sizing:border-box ;'> Birinapant is an IAP dimer inhibitor developed by Tetralogic Pharmaceuticals in the United States.
In a phase II clinical trial of birinapant combined with irinotecan in the treatment of relapsed/refractory colorectal cancer (NCT01188499), 51 test patients were divided into KRAS-MT (mutation) group and KRAS-WT according to the KRAS gene classification (Wild) group.
In the first course of treatment, the patients were randomized to receive irinotecan (350 mg · m-2) + birinapant (5.
6 mg · m-2) and irinotecan (350 mg · m-2) + birinapant (11 mg · m- 2) Intravenous fluid therapy.
In the second course of treatment, the dose of birinapant was further increased, 22 mg·m-2 was the maximum tolerated dose, and dose-limiting toxicity appeared at 35 mg·m-2.
Patients in the KRAS-MT group received irinotecan (350 mg · m-2) + birinapant (5.
6~22 mg · m-2), irinotecan (350 mg · m-2) + birinapant (22~35 mg · m- 2) Treatment; patients in the KRAS-WT group received irinotecan (350 mg · m-2) + birinapant (11~22 mg · m-2), irinotecan (350 mg · m-2) + birinapant (22~ 35mg·m-2) treatment.
In a phase II clinical trial of birinapant combined with irinotecan in the treatment of relapsed/refractory colorectal cancer (NCT01188499), 51 test patients were divided into KRAS-MT (mutation) group and KRAS-WT according to the KRAS gene classification (Wild) group.
In the first course of treatment, the patients were randomized to receive irinotecan (350 mg · m-2) + birinapant (5.
6 mg · m-2) and irinotecan (350 mg · m-2) + birinapant (11 mg · m- 2) Intravenous fluid therapy.
In the second course of treatment, the dose of birinapant was further increased, 22 mg·m-2 was the maximum tolerated dose, and dose-limiting toxicity appeared at 35 mg·m-2.
Patients in the KRAS-MT group received irinotecan (350 mg · m-2) + birinapant (5.
6~22 mg · m-2), irinotecan (350 mg · m-2) + birinapant (22~35 mg · m- 2) Treatment; patients in the KRAS-WT group received irinotecan (350 mg · m-2) + birinapant (11~22 mg · m-2), irinotecan (350 mg · m-2) + birinapant (22~ 35mg·m-2) treatment.
