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CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
More recently, Chen et al. reported highly synergistic interactions between roscovitine and the Bcl-2 antagonist ABT-737 in human leukemia cells (85). The mechanism responsible for this interaction was determined as Mcl-1 down-regulation mediated by roscovitine, which cooperated with ABT-737 in the disruption of the function of Bcl-xL to unleash Bak and activate Bax. In view of evidence of in vivo activity of agents like ABT-737 in murine models of lymphoma (86), the concept of combining Bcl-2 antagonists with CDK inhibitors warrants further attention.
Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
The Bcl-2 proteins are a group of apoptosis suppressor genes, which include Bcl-2, Bcl-XL, Bim, and mcl-1 (Hata et al., 2015). These proteins serve to prolong the cellular life cycle, during a cancerous mutation however, overexpression of these genes may up survival of the metastatic cell due the cell cycle arrest at the G0 phase. Prior studies have identified these genes as viable drug targets. Mérino et al. (2012) reported that ABT-737 &ABT-263 (navitoclax), are highly effectual inhibitors of Bcl-2 proteins; however, these drugs exhibit lower affinity to Mcl-1 protein which prevents apoptosis (Mérino et al., 2012). Thus, further research to search for a more selective agent of which can be more combatant in cancer types with elevated Mcl-1 levels is preferred. When cancer forms, oncogenes or tumor suppressor genes may specify for proteins that upregulate the survival of a mutant cell. This ultimately leads to cancer, in some scenarios the malignant cell is capable in forming vasculature to improve blood flow to itself and even perhaps use the body’s own circulatory organ as a vector to spread (Science Daily, 2018). Therapeutic treatments with marinopyrroles are required for the initiation of apoptosis and counter these pro-survival proteins. The cellular process of apoptosis is caspase-dependent, which are cysteine proteases; their activation is facilitated through two pathways, extrinsic (Ashkenazi, 2015) or intrinsic (Elumalai et al., 2012). The extrinsic pathway is permitted by a death receptor, whereas the intrinsic pathway is derived from mitochondrial influence. Upon activation, caspases exert their effects via proteolytic cleavage; the resulting occurrences being DNA destruction and blebbing of the cellular membrane, both of which are characteristics of apoptosis in either circumstance of activation. Bcl-2 proteins are highly involved with the intrinsic mode of apoptotic activation by having regulatory possessions on the mitochondrial outer membrane permeabilization (MOMP); subsequently cytochrome c and Smac are released from the mitochondrial cytosol (Shamas-Din et al., 2013). The apoptogenic factors upon release increase the activation of caspases, inducing cell death.
The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma
Published in Expert Review of Anticancer Therapy, 2021
Surein Arulananda, Erinna F Lee, W Douglas Fairlie, Thomas John
Critical to the discovery of drugs targeting BCL-2 pro-survival proteins was the elucidation of their structures bound to various BH3 domain sequences. These all showed a conserved mode of interaction involving the hydrophobic groove in the pro-survival molecules [59] and paved the way for the development of compounds that mimic this interaction (hence are called ‘BH3-mimetics’) Figure 4A. The first-in-class BH3-mimetic was ABT-737, which potently binds to BCL-2, BCL-XL, and BCL-W (Ki < 1 nM) and was shown to kill cancer cells in a BAK- and BAX-dependent manner [60]. Importantly, ABT-737 demonstrated single agent and synergistic combination activity in a variety of tumor cells, including small-cell lung cancer, leukemia, and lymphoma, both in vitro and in vivo [61,62].
Enhancing venetoclax activity in hematological malignancies
Published in Expert Opinion on Investigational Drugs, 2020
Despite these setbacks, pre-clinical studies indicated that BCL2 inhibition through the development of small molecules that mimic the BCL2 homology domain 3 (BH3) found in all pro-apoptotic BCL2 family proteins represented a potentially more effective approach. ABT-737, developed through fragment-based design, was the first-in- class BH3 mimetic to be developed that binds BCL2, BCLXL, and BCLW with high affinity as well as weakly to other BCL2 family members including MCL1 [3]. In in vivo studies employing primary cancer cells, including those of hematopoietic origin, ABT-737 effectively induced apoptosis [3,4], However, limited bioavailability and the need for parenteral administration hindered further clinical development. Subsequently, navitoclax (ABT-263), an orally bioavailable derivative of ABT-737, was then developed. Navitoclax showed efficacy in early phase clinical trials alone or in combination with Rituximab [5–7]. However, thrombocytopenia (grade 3 or higher) was reported in 18–33% of patients treated with navitoclax [6], presumably due to on-target effects related to BCLXL inhibition [8].
Clinical management of mantle cell lymphoma in the elderly
Published in Expert Opinion on Pharmacotherapy, 2019
Piotr Smolewski, Dominika Rydygier, Tadeusz Robak
Another group of potential treatment targets is the prosurvival Bcl-2 protein family, whose members are constitutively overexpressed in MCL patients with poor response to standard chemotherapy and with chemoresistance [110,111]. ABT-737 is a novel agent that selectively binds to Bcl-2 and Bcl-xL, displaces pro-apoptotic BH3-only from Bcl-2 or Bcl-xL, resulting in the activation of Bax, Bak and downstream caspases [84]. Ongoing clinical studies have shown that ABT-737 is highly effective in monotherapy against both leukemia and lymphoma cell lines. In addition, in vitro and in vivo studies have found ABT-737 to demonstrate strongly cytotoxic properties in MCL cell lines [112]. Studies investigating various Bcl2-inhibitors, such as ABT-199 (venetoclax), obatoclax or other Bcl2 – protein inhibitors are ongoing [113]. One such study [70] has found Venetoclax to be well tolerated for MCL patients, and the recommended single-agent dose for future clinical trials is 800 mg. The overall response rate was 75% and estimated median PFS was 14 months for patients with MCL.