2020
DOI: 10.1038/s41467-020-15742-7
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Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Abstract: Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity f… Show more

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Cited by 35 publications
(25 citation statements)
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“…Drugs such as lenalidomide and pomalidomide can enhance antitumor ILC behavior as well ( 159 , 160 ). Bryostatins are protein kinase C modulators that are currently being engineered to improve CAR NK functionality ( 161 ). These and many other drugs have the potential to broadly or specifically activate NK cells or ILCs in addition to other immune cells within the TME.…”
Section: Discussion: Bioengineered Immunomodulators and Targeted Drug Delivery As New Frontiersmentioning
confidence: 99%
“…Drugs such as lenalidomide and pomalidomide can enhance antitumor ILC behavior as well ( 159 , 160 ). Bryostatins are protein kinase C modulators that are currently being engineered to improve CAR NK functionality ( 161 ). These and many other drugs have the potential to broadly or specifically activate NK cells or ILCs in addition to other immune cells within the TME.…”
Section: Discussion: Bioengineered Immunomodulators and Targeted Drug Delivery As New Frontiersmentioning
confidence: 99%
“…Shortly after their discovery, PKCs were identified as cellular receptors for tumor-promoting phorbol esters 12 that bind C1 domains in lieu of DAG. These observations, combined with the central roles executed by PKCs in intracellular signaling established their DAG-sensing function as an attractive target for therapeutic intervention, with considerable promise in the treatment of Alzheimer's disease 13 , HIV/AIDS 14,15 , and cancer 16,17 . However, the structural basis of DAG recognition by the C1 domains remained elusive, and the strategies for therapeutic agent design deployed to date all relied on modeling studies (reviewed in 18 ) based on the single available crystal structure of the C1 domain complexed to a ligand that does not activate PKC 19 .…”
Section: Introductionmentioning
confidence: 99%
“…Bryo-1 has anti-tumorigenic properties and has been tested in multiple human clinical trials of solid and hematologic malignancies (Clamp and Jayson, 2002). It is currently under investigation in pre-clinical or clinical studies of Alzheimer's disease (Farlow et al, 2019;clinicaltrials.gov, NCT03560245), HIV latency reversal (Bullen et al, 2014;Gutierrez et al, 2016;Laird et al, 2015;Sloane et al, 2020), and antigenic stimulation to augment CAR-T immunotherapy (Hardman et al, 2020;Ramakrishna et al, 2019).…”
Section: Introductionmentioning
confidence: 99%
“…We recently reported a scalable synthesis of bryo-1 that addresses the clinical supply problem and provides bryo-1 in quantities that enable the first-ever synthetic access to potentially efficacious close-in precursors and derivatives (Wender et al, 2017). Prior computational, synthesis, and assay work has established the functional importance of the distinct structural elements of bryo-1, identifying pharmacophoric elements critical for PKC binding and regulatory elements that impact ternary interactions with the plasma membrane ( Figure 1A) (Hardman et al, 2020;Ryckbosch, Wender, and Pande, 2017;Wender et al, 1986 and1988;Yang et al, 2018). Three hydrogen-bonding functionalities around the C-ring (C1 carbonyl, C19 hemiketal, and C26 hydroxyl) are critical for PKC binding, whereas the A and B rings determine interactions with the plasma membrane and regulate PKC translocation and downstream functions in biological systems.…”
Section: Introductionmentioning
confidence: 99%
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