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Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
Proteasome inhibitors block cancer progression by interfering with the degradation of regulatory proteins. It is assumed that the ratio of pro- and anti-apoptotic proteins within a cell becomes disturbed, thereby resulting in an increased sensitivity to apoptosis (33). Additionally, proteasome inhibition can cause apoptosis by directly affecting the levels of various specific proteins like inhibitory protein IκB, thereby inactivating the survival protein nuclear factor κB (NF-κB) (34,35). Proteasomal inhibition can also lead to increased activity of p53 and proapoptotic Bax protein, and accumulation of cyclin-dependent kinase inhibitors like p27 and p21 (27,36–38).
Approach to risk stratification in cardio-oncology
Published in Susan F. Dent, Practical Cardio-Oncology, 2019
Christopher B. Johnson, Gary Small, Angeline Law, Habibat Garuba
A 64-year-old patient is diagnosed with multiple myeloma and achieves complete remission on a proteasome inhibitor. After 2 years on therapy, he develops severe hypertension refractory to maximum doses of four antihypertensives. Imaging reveals bilateral renal artery stenosis, and he undergoes renal artery angioplasty with perfect angiographic results. Subsequently, his hypertension is well controlled on only two medications. He is referred to cardio-oncology to determine the safety of resuming proteasome inhibitor therapy for his multiple myeloma. His risk factors include hypertension, remote smoking totaling 20 pack years, and dyslipidemia. At the time of his assessment, he has no exertional symptoms, and no history of cardiovascular disease besides his renal artery stenosis with bilateral renal artery angioplasty. Medications at the time of assessment include ASA 81 mg daily, perindopril 8 mg, and indapamide 2.5 mg daily. Physical examination is normal, with a BMI of 23, waist circumference of 80 cm, BP 124/74, no carotid or abdominal bruits, a normal ankle/brachial index, and no extra heart sounds or murmurs.
Drug profiles: generic names A-Z
Published in Jerome Z. Litt, Neil H. Shear, Litt's Drug Eruption & Reaction Manual, 2017
Indications: Multiple myeloma in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are doublerefractory to a PI and an immunomodulatory agent
Small molecules as kinetoplastid specific proteasome inhibitors for leishmaniasis: a patent review from 1998 to 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Mohd Imran, Shah Alam Khan, Ahmed Subeh Alshrari, Mahmoud Mudawi Eltahir Mudawi, Mohammed Kanan Alshammari, Aishah Ali Harshan, Noufah Aqeel Alshammari
The updated patent search was performed on 31 December 2021. The keywords (leishmaniasis, kinetoplastid, proteasome, chymotrypsin) were selected for the patent search in the database of Sci-finder, Espacenent, WIPO, and USPTO. A combination of these keywords was used for the patent search (Scheme 1). The exact structure search was also performed for LXE408, GSK3494245, and GNF6702 in Sci-finder. The patents/patent applications that exemplify the proteasome inhibition data in the description part; claim proteasome inhibitory activity of the compounds, or the description states that the disclosed compounds are proteasome inhibitors, were analyzed and included in this review. The patents/patent applications that do not provide information (explicitly or implicitly) about the proteasome inhibitory activity of the compounds were excluded from the final list.
Investigational treatment options in phase I and phase II trials for relapsed or refractory acute lymphoblastic leukemia in pediatric patients
Published in Expert Opinion on Investigational Drugs, 2021
Julie M. Asare, Cara A. Rabik, Bradley Muller, Patrick A. Brown, Stacy Cooper
Bortezomib is a selective inhibitor of the ubiquitin proteasome pathway (UPP) [80]. Bortezomib specifically inhibits the 26S proteasome, which is an ATP-dependent multi-subunit protein that degrades proteins involved in cell cycle regulation, transcription factor activation, apoptosis, and cell trafficking [81]. Proteasome inhibition alters the ratio of pro-apoptotic and anti-apoptotic proteins within a cell and has been seen to increase the cell’s sensitivity to apoptosis [82]. Abnormal proteasome-dependent proteolysis is seen in malignancies, including leukemia, leading to uncontrolled cell division. Preclinical studies show that proteasome inhibition leads to apoptosis in leukemia cells lines and xenotransplantation [83,84]. In addition, it is seen to have synergistic effected when combined with corticosteroids and doxorubicin in vitro and in vivo [84].
Proteasome inhibition for the treatment of glioblastoma
Published in Expert Opinion on Investigational Drugs, 2020
Patrick Roth, Warren P. Mason, Paul G. Richardson, Michael Weller
Bortezomib was identified from a screening of several boronic acid peptide small molecule analogues that were tested against a panel of tumor cell lines [32]. It acts as a reversible inhibitor of the proteasome’s chymotrypsin-like activity but has limited activity against the other enzymatic activities of the proteasome. Following extensive preclinical testing, the drug was the first proteasome inhibitor to enter clinical trials. Bortezomib was particularly active against multiple myeloma and was systemically investigated in early clinical studies followed by trials with larger patient cohorts in late and early relapse followed by newly-diagnosed disease. Upon successful completion of both phase 2 and phase 3 studies, the drug was approved by the FDA and other regulatory authorities for the treatment of patients with relapsed multiple myeloma [33–35] and later for patients with newly diagnosed disease [36]. Furthermore, the drug was subsequently approved for the treatment of patients with mantle cell lymphoma [37]. In contrast to its strong clinical activity against hematological malignancies as well as a substantial body of literature describing convincing anti-tumor activity in various preclinical models, bortezomib displayed minimal or no activity against solid tumors in larger trials [38]. Bortezomib is mainly metabolized through the liver. Side effects include nausea, diarrhea, fatigue, thrombocytopenia and peripheral neuropathy [39]. The latter may originate from a non-proteasome-dependent mechanism with nonselective binding properties of the drug, including serine proteases and other molecules [40].