Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity

Perez, Heidi L.; Chaudhry, Charu; Emanuel, Stuart L.; Fanslau, Caroline; Fargnoli, Joseph; Gan, Jinping; Kim, Kyoung S.; Lei, Ming; Naglich, Joseph G.; Traeger, Sarah C.; Vuppugalla, Ragini; Wei, Donna; Vite, Gregory D.; Talbott, Randy; Borzilleri, R. M.

doi:10.1021/jm501482t

Cited by 16 publications

(11 citation statements)

References 25 publications

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“…It also resulted in degradation of cIAP1 and induced apoptosis in breast cancer cell lines (Hennessy, et al, 2013). Several other bivalent SMAC mimetics have now been developed by different chemical modifications between the linker regions and were reported to be highly potent (Zide Chen, et al, 2018;Yuefeng Peng, et al, 2011;Perez, et al, 2015;Sheng, et al, 2013).…”

Section: Smac Mimeticsmentioning

confidence: 99%

The Multiple Roles of the IAP Super-family in cancer

Kumar

Fairmichael

Longley

et al. 2020

Pharmacology & Therapeutics

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The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes.IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor B (NFB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.

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Section: Smac Mimeticsmentioning

confidence: 99%

The Multiple Roles of the IAP Super-family in cancer

Kumar

Fairmichael

Longley

et al. 2020

Pharmacology & Therapeutics

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“…Perez et al [148] described a series of heterodimeric bivalent SMAC mimetics analogous to 17, which Kim et al had previously reported as a polyamine-substituted analog. [149] The original compound 17 can induce cell death in the HCT116/ VM46 cell line, so Perez et al attempted to boost its efficacy by shortening the linker compound 18 or removing it entirely compound 19.…”

Section: Bivalent Small-molecule Smac Mimetics As Iap Antagonistsmentioning

confidence: 99%

“…Perez et al . described a series of heterodimeric bivalent SMAC mimetics analogous to 17 , which Kim et al.…”

Section: Bivalent Small‐molecule Smac Mimetics As Iap Antagonistsmentioning

confidence: 99%

Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Zhu

Liu

et al. 2019

ChemMedChem

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Inhibitors of apoptosis proteins (IAPs) inhibit caspase activity, allowing various cancers to reduce programmed cell death (apoptosis) and resist drug treatment. The second mitochondrial‐derived activator of caspases (SMAC) protein is an endogenous IAP antagonist, which can be considered as a potential anticancer therapy. Small‐molecule SMAC mimetics based on the Ala‐Val‐Pro‐Ile motif have been validated as potent IAP antagonists. In particular, most bivalent SMAC mimetics, which target both the baculovirus IAP repeat 2 (BIR2) and BIR3 domains in X‐linked IAP (XIAP), antagonize IAPs better than the corresponding monovalent mimetics. Here we focus on strategies for designing bivalent small‐molecule SMAC mimetics and progress in using them to antagonize IAPs. We also consider their clinical potential. Our discussion will hopefully help guide further study of these interesting mimetics.

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“…Unnatural amino acids (UAAs) are fundamental building blocks of modern medicinal chemistry, because their readily functionalized amine and carboxyl groups can be attached to chiral central core of functional molecules along with one or two potentially diverse side chains . L‐ tert ‐leucine which is sterically bulky, inflexible, and hydrophobic is the most common unusual alkyl amino acid found in drugs, such as the central residue of JAK3‐selective kinase inhibitor developed by Roche et al Two α‐aminobutyric acid residues are contained in “birinapant,” a second‐generation bivalent antagonist of IAP proteins that is currently undergoing clinical development for cancer treatment . Besides application in small molecules, UAAs are also unique building blocks for peptide‐based drugs, such as phenylglycine in pasireotide used for the treatment of Cushing's disease, phenylglycine and D‐2‐aminobutyric acid in cyclic depsipeptide quinupristin .…”

Section: Introductionmentioning

confidence: 99%

Rational Engineering ofBacillus cereusLeucine Dehydrogenase Towards α-keto Acid Reduction for Improving Unnatural Amino Acid Production

et al. 2018

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Unnatural amino acids (UAAs) play a key role in modern medicinal chemistry such as small molecules and peptide-based drugs with fast-growing markets. Low efficiency for natural enzymes including leucine dehydrogenase (LeuDH, EC1.4.1.9) are one major challenge for UAA production. Here, rational engineering of LeuDH from Bacillus cereus with a structure-based design approach is studied. The results achieve higher enzymatic activity and stability toward α-keto acid reduction by improving the hydrophobic and rigidity of enzymatic substrate entrance tunnel. High catalytic efficiency for variant E116V is associated with the presence of more hydrophobic tunnels that allows easy substrate diffusion, which is confirmed in absorbance spectroscopy study. For variant T45M/E116V, melting temperature and half-lives of thermal inactivation at 60 °C is 62.8 °C and 29.2 h, respectively, much higher than 48.4 °C and 3.4 h of wild type. Structural analysis indicates that an additional hydrogen bond in β5 fold is formed in variant T45M, which results in a more rigid β5 fold leading to better stability. Furthermore, asymmetric synthesis of α-amino acids with coenzyme regeneration reveals higher productivities for variant T45M/E116V. This study indicates the importance of substrate entrance tunnel for enzymatic activities and stability, the engineered LeuDH would better serve UAA production.

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Discovery of Potent Heterodimeric Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Sustained Antitumor Activity

Cited by 16 publications

References 25 publications

The Multiple Roles of the IAP Super-family in cancer

The Multiple Roles of the IAP Super-family in cancer

Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

Rational Engineering ofBacillus cereusLeucine Dehydrogenase Towards α-keto Acid Reduction for Improving Unnatural Amino Acid Production

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