mipsagargin (G-202) / Rebus - LARVOL DELTA

Thapsigargin and its prodrug derivatives: exploring novel approaches for targeted cancer therapy through calcium signaling disruption. (PubMed, Med Oncol) - "However, the completion of clinical trials with no ongoing studies suggests that the viability of mipsagargin and other prodrugs remains uncertain, especially in light of the toxicities observed. While thapsigargin and its derivatives present a potential pathway in cancer treatment, their future role in oncology requires careful re-evaluation."

Journal • Review • Oncology

Thapsigargin: a promising natural product with diverse medicinal potential - a review of synthetic approaches and total syntheses. (PubMed, Org Biomol Chem) - "Mipsagargin, a prodrug derived from thapsigargin, is under clinical trials for the treatment of glioblastoma. Limited natural availability and challenging synthesis have prompted research into new synthetic pathways. This review discusses significant synthetic approaches and total syntheses of thapsigargin reported to date."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Gynecology • Infectious Disease • Infertility • Musculoskeletal Pain • Novel Coronavirus Disease • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Sexual Disorders • Solid Tumor

Computational models to understand the diverse factors controlling reactivity and selectivity in Rh-catalyzed asymmetric Pauson-Khand reactions (ACS-Sp 2024) - "Herein, the rhodium-catalyzed asymmetric Pauson-Khand reaction (PKR) of 1,6-enynes with three different ligands (( S )-BINAP, ( R )-MonoPhos, and CO) was examined experimentally and computationally. Experimental temperature, CO concentration, and translational entropy corrections were incorporated into the DFT calculations to accurately describe the preference of 4-coordinated oxidative cyclization transition state in the enantioselectivity determining step. In additional studies of the allenic Pauson-Khand reaction (APKR), computational modeling of the ligand-substrate interactions in the transition state enabled the rational design of complex substrates with more direct synthetic routes to natural products Thapsigargin and Mipsagargin."

Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status. (ASCO 2017) - P1/2,P2; "Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. ALK fusions were detected in plasma in < 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation."

Biosimilar • Non Small Cell Lung Cancer

The endoplasmic reticulum membrane protein Sec62 as potential therapeutic target in SEC62 overexpressing tumors. (PubMed, Front Physiol) - "Therefore, murine tumor models for tumor growth or metastasis were evaluated with respect to their responsiveness to treatment with a mipsagargin analog (thapsigargin), or trifluoperazine, which had previously been in clinical use for the treatment of schizophrenia, or with the combination of both drugs. So far, no additive effect of the two drugs was observed but trifluoperazine had an inhibitory effect on tumor growth and metastatic potential in the models. Here, we review the state of affairs."

Journal • Review • CNS Disorders • Oncology • Psychiatry • Schizophrenia

Mipsagargin: The Beginning-Not the End-of Thapsigargin Prodrug-Based Cancer Therapeutics. (PubMed, Molecules) - "The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing."

Journal • Review • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FAP • FOLH1 • KLK2 • KLK3

Apatinib in patients with adenocarcinoma of stomach or gastroesophageal junction: A prospective, multicenter, non-interventional study (Ahead-G202). (ASCO 2018) - P=N/A; "In the real world, pts were most likely given apatinib by the dose of 500mg or less. The dose of 425-500mg showed similar efficacy to Phase clinical trial (850mg), while the mOS of 250mg was shorter. No new adverse events had been identified in this trial."

Clinical • Observational data • Gastric Cancer

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer (ESMO 2019) - P=N/A; "Apatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC. Clinical trial identification: AHEAD-G202 (NCT02668380)."

Clinical

From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development. (PubMed, Prog Chem Org Nat Prod) - "Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus."

Clinical • Journal • Oncology

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer. (PubMed, Transl Oncol) - P=N/A | "Apatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer."

Clinical • Journal • Anorexia • Gastric Cancer • Gastrointestinal Cancer • Hypertension • Oncology • Solid Tumor • AFP • CEACAM5

Thapsigargin-From Traditional Medicine to Anticancer Drug. (PubMed, Int J Mol Sci) - "This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, however, hampered due to high toxicity of this compound to normal cells. In this review, we summarized the recent knowledge on the biological activity and molecular mechanisms of thapsigargin action and advances in the synthesis of less-toxic thapsigargin derivatives that are being developed as novel anticancer drugs."

Journal • Review • Gynecology • Infertility • Musculoskeletal Pain • Oncology • Pain • Respiratory Diseases • Sexual Disorders

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin. (PubMed, Biomolecules) - "Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin."

Journal • Oncology

Molecular Characterization of Glucose-6-Phosphate Dehydrogenase: Do Single Nucleotide Polymorphisms Affect Hematological Parameters in HIV-Positive Patients? (PubMed, J Trop Med) - "Among G6PD-deficient HIV patients, the prevalence of G202/A376 SNPs is 19.2%. The 376A ⟶ G mutation is associated not only with lower RBC count but also with higher MCV and MCH, whereas the 202G ⟶ A mutation is associated with higher MCV compared to the normal G6PD population."

Clinical • Journal • Hematological Disorders • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders

Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours. (PubMed) - Br J Cancer - "Mipsagargin demonstrated an acceptable tolerability and favourable pharmacokinetic profile in patients with solid tumours."

Journal • Biosimilar • Oncology • Renal Disease

Genspera enters national phase with patent application for injectable prodrug formulations (PRNewswire) - "GenSpera...announced today that the patent application "Injectable Cancer Compositions" has entered the national phase application process in 17 countries and regions, including Europe, Eurasia, Japan, China, Brazil and the United States. When awarded, the resulting patent application will extend the exclusivity period for GenSpera's core intellectual property around its entire platform technology, including its lead drug candidate, mipsagargin, until 2033."

Anticipated patent • Prostate Cancer

Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non-Small-Cell Lung Cancer: Analysis and Literature Review. (PubMed) - Clin Lung Cancer - "Some acquired ALK mutations may cause co-resistance to other ALK inhibitors. Re-biopsy for ALK mutation analysis might be suggested prior to choosing a second-line ALK inhibitor treatment."

Journal • Biosimilar • Non Small Cell Lung Cancer • Oncology

An open label, multicenter, noninterventional study of apatinib in advanced gastric cancer patients (AHEAD-G202). (PubMed, Ther Adv Med Oncol) - P=N/A | "Lower daily doses of apatinib achieved comparable OS and PFS versus higher daily doses of apatinib while maintaining a more benign safety profile in advanced gastric cancer patients. ClinicalTrials.gov identifier: NCT02668380."

Clinical • Journal • Observational data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Safety and effectiveness of apatinib in patients with previously treated metastatic gastric cancer: a sub-analysis from the real-world study of apatinib for gastric cancer treatment (AHEAD-G202). (PubMed, Am J Cancer Res) - "We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice."

Clinical • Journal • Real-World Evidence • Fatigue • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Synthesis of the carbocyclic core of thapsigargin using the asymmetric allenic Pauson–Khand reaction (ACS-Sp 2020) - "Mipsagargin, a prodrug of the potent SERCA inhibitor thapsigargin (Tg), recently completed phase II clinical trials for several types of cancer...The functional group at C2 will direct the desired stereochemistry at the remaining chiral centers. Our progress towards these goals will be presented."

Synthesis of the carbocyclic core of thapsigargin using the asymmetric allenic Pauson–Khand reaction (ACS-Sp 2020) - "Mipsagargin, a prodrug of the potent SERCA inhibitor thapsigargin (Tg), recently completed phase II clinical trials for several types of cancer...The functional group at C2 will direct the desired stereochemistry at the remaining chiral centers. Our progress towards these goals will be presented."

A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma. (PubMed, Cancers (Basel)) - " Mipsagargin is relatively well tolerated and promotes prolonged disease stabilization in patients with advanced HCC that had progressed on prior treatment with sorafenib. A significant decrease in K upon treatment suggests mipsagargin reduces blood flow in hepatic lesions."

Clinical • Journal • P2 data