Article
Oncology
Christian Schwarzenbach, Larissa Tatsch, Juliana Brandstetter Vilar, Birgit Rasenberger, Lea Beltzig, Bernd Kaina, Maja T. Tomicic, Markus Christmann
Summary: Malignant glioma treatment relies on O-6-methylguanine induction by TMZ, but most glioma cells evade apoptosis and become senescent post-TMZ exposure. Inhibiting SCAP factors, c-IAP2 and Bcl-2, enhances TMZ toxicity and reduces senescent cell protection. BV6 and venetoclax act as senolytic agents in glioblastoma cells post-TMZ exposure, increasing cell death and showing synergistic effects.
Article
Oncology
Yusuke Shibuya, Kei Kudo, Kristen P. Zeligs, David Anderson, Lidia Hernandez, Franklin Ning, Christopher B. Cole, Maria Fergusson, Noemi Kedei, John Lyons, Jason Taylor, Soumya Korrapati, Christina M. Annunziata
Summary: The combination of SMAC mimetics and HDAC inhibitors is a promising strategy for cancer treatment. HDAC inhibitors stimulate TNF-alpha production, which synergizes with SMAC mimetics. Overexpression of IAP proteins is associated with poor survival in ovarian cancer, and SMAC mimetics restore apoptotic pathways by suppressing IAP functions.
Review
Biochemistry & Molecular Biology
Raffaele Frazzi
Summary: BIRC3 and BIRC5 are members of the IAPs family, with the former potentially promoting survival in cancer cells while the latter is often considered an anti-apoptotic molecule. Their roles in different types of tumors vary and their potential as therapeutic targets is still under investigation.
CELL AND BIOSCIENCE
(2021)
Article
Chemistry, Medicinal
Inhwan Bae, Daejin Kim, Jaeyul Choi, Jisook Kim, Minjeong Kim, Bokyung Park, Young Hoon Kim, Young Gil Ahn, Ha Hyung Kim, Dae Kyong Kim
Summary: The newly designed and synthesized bivalent analogue 27 showed significant increase in cellular activity and caused substantial tumor regressions in MDA-MB-231 xenograft model, indicating its promising potential as an effective anti-tumor agent.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Adam H. Tencer, Yucong Yu, Sebastien Z. Causse, Grant R. Campbell, Brianna J. Klein, Hongwen Xuan, Jessy Cartier, Mark A. Miles, Nitika Gaurav, Aymeric Zadoroznyj, Tina A. Holt, Hong Wen, Christine J. Hawkins, Stephen A. Spector, Laurence Dubrez, Xiaobing Shi, Tatiana G. Kutateladze
Summary: The tumor suppressor gene BIRC2 regulates cell death and survival pathways by binding to histone H3 tail and accumulating in the nucleus. Overexpression of BIRC2 delays DNA damage repair and cell cycle progression, while a small molecule inhibitor LCL161 disrupts the association of BIRC2 with H3, leading to cell death in cancer cells and degradation of BIRC2 in HIV-1-infected T cells.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Hematology
Naveen Pemmaraju, Bing Z. Carter, Prithviraj Bose, Nitin Jain, Tapan M. Kadia, Guillermo Garcia-Manero, Carlos E. Bueso-Ramos, Courtney D. DiNardo, Sharon Bledsoe, Naval G. Daver, Uday Popat, Marina Y. Konopleva, Lingsha Zhou, Sherry Pierce, Zeev E. Estrov, Gautam M. Borthakur, Maro Ohanian, Wei Qiao, Lucia Masarova, Xuemei Wang, Po Yee Mak, Jorge Cortes, Elias Jabbour, Srdan Verstovsek
Summary: Treatment with SMAC mimetic LCL161 in high-risk and treatment-resistant MF patients showed a 30% objective response rate, with 6 patients achieving clinical improvement in anemia. The median overall survival was 34 months, and while there were some adverse events, two deaths during the study period were unrelated to the study drug.
Article
Immunology
Katherine S. Ventre, Kevin Roehle, Elisa Bello, Aladdin M. Bhuiyan, Tamara Biary, Stephanie J. Crowley, Patrick T. Bruck, Max Heckler, Patrick J. Lenehan, Lestat R. Ali, Courtney T. Stump, Victoria Lippert, Eleanor Clancy-Thompson, Winiffer D. Conce Alberto, Megan T. Hoffman, Li Qiang, Marc Pelletier, James J. Akin, Michael Dougan, Stephanie K. Dougan
Summary: Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types due to inadequate T cell priming. cIAP1/2 antagonists have pleiotropic beneficial effects on antitumor immunity, including increased activation and control of tumor growth, synergy with multiple immunotherapy modalities, and immunologic memory. This study confirms the importance of T cell-dependent antitumor immunity and provides insights into how rare T cells coordinate downstream immune responses.
JOURNAL OF IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Yuen Lam Dora Ng, Alesa Bricelj, Jacqueline A. Jansen, Arunima Murgai, Kirsten Peter, Katherine A. Donovan, Michael Guetschow, Jan Kroenke, Christian Steinebach, Izidor Sosic
Summary: Proteolysis targeting chimeras (PROTACs) recruit E3 ubiquitin ligases to degrade disease-causing proteins. Heterobifunctional PROTACs consisting of an IAP antagonist linked to von Hippel-Lindau or cereblon ligands effectively deplete cellular IAPs. These compounds show superior inhibition of cancer cell viability compared to antagonists and provide valuable tools for studying the biological roles of IAPs and E3 targeting therapies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Immunology
Arya Afsahi, Christopher M. M. Silvestri, Allyson E. E. Moore, Carly F. F. Graham, Kaylyn Bacchiochi, Martine St-Jean, Christopher L. L. Baker, Robert G. G. Korneluk, Shawn T. T. Beug, Eric C. C. LaCasse, Jonathan L. L. Bramson
Summary: The SMAC mimetic drug LCL161 enhances T cell function by inhibiting IAP proteins and activating the non-canonical NF-kappa B pathway. However, LCL161 does not improve T cell anti-tumor function when interacting with myeloma cells, possibly due to sensitization of T cells to Fas-mediated apoptosis.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
James Schiemer, Reto Horst, Yilin Meng, Justin I. Montgomery, Yingrong Xu, Xidong Feng, Kris Borzilleri, Daniel P. Uccello, Carolyn Leverett, Stephen Brown, Ye Che, Matthew F. Brown, Matthew M. Hayward, Adam M. Gilbert, Mark C. Noe, Matthew F. Calabrese
Summary: Heterobifunctional chimeric degraders are ligands that recruit target proteins to E3 ubiquitin ligases to induce protein degradation. This study characterized degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1 using biochemical, biophysical and structural studies, revealing new insights and showing that increased ternary complex stability or rigidity does not always correlate with increased degradation efficiency.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Federica Cossu, Simone Camelliti, Daniele Lecis, Luca Sorrentino, Maria Teresa Majorini, Mario Milani, Eloise Mastrangelo
Summary: Inhibitors of apoptosis proteins (IAPs) are important targets in cancer research, and the compound FC2 has been identified as a potential lead compound for the development of new IAP-antagonists for cancer treatment. FC2 can disrupt pro-survival pathways in cancer cells and induce cancer cell death, showing promise for combination therapy with other agents.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Review
Chemistry, Multidisciplinary
Yung-Chieh Chang, Chun Hei Antonio Cheung
Summary: This article reviews the anti-cancer potency and novel molecular targets of Smac mimetics, highlighting their ability to induce apoptosis, arrest cell cycle, induce necroptosis, and trigger an immune response. Clinical trials have evaluated the safety and effectiveness of Smac mimetics, with promising results when combined with chemotherapy compounds. Recent studies have uncovered new anti-cancer mechanisms of Smac mimetics, indicating further exploration is needed for potential modification and combination therapies.
APPLIED SCIENCES-BASEL
(2021)
Article
Biotechnology & Applied Microbiology
Erin M. Witkop, Dina A. Proestou, Marta Gomez-Chiarri
Summary: The expansion of the Inhibitor of Apoptosis (IAP) gene family plays important roles in regulating apoptosis and immunity in oysters. The study reveals unprecedented diversity of IAPs in oysters, with novel protein domains and architectures. This expansion facilitates complex and nuanced regulation of apoptosis and other immune responses in oysters.
Article
Biochemistry & Molecular Biology
Shaikh Maryam Ghufran, Sachin Sharma, Sampa Ghose, Subhrajit Biswas
Summary: TNF alpha induces cell survival in activated hepatic stellate cells (HSCs) through NF-kappa B signaling, and cIAP2 plays a regulatory role in this process. Inhibition of cIAP2 can attenuate TNF alpha-induced cell viability and activation of the NF-kappa B signaling pathway, and it has anti-proliferative effects on activated HSCs. Targeting cIAP2 in the NF-kappa B signaling pathway may be a promising approach for the treatment of liver fibrosis.
MOLECULAR BIOLOGY REPORTS
(2023)
Article
Multidisciplinary Sciences
Franziska Mueller, Alexandra Friese, Claudio Pathe, Richard Cardoso da Silva, Kenny Bravo Rodriguez, Andrea Musacchio, Tanja Bange
Summary: This study reveals that by inhibiting the N-α-acetyltransferase NatA, proteins with IBM-like motifs can be transformed into efficient IAP binders, leading to cellular apoptosis. Thus, acetylation of the amino-terminal IBM-like motifs in NatA substrates serves as a protective mechanism against IAPs.
Review
Immunology
Xiangye Zhao, Kewei Ma, Xiaobo Ma, Xu Wang, Chao Sun, Shi Qiu, Ye Guo, Zhiguang Yang, Yunpeng Liu, Yinghui Xu
Summary: Immunotherapy may lead to pseudoprogression, where tumors initially grow but shrink with continued treatment. This article reports a case of pseudoprogression in a lung cancer patient receiving immunotherapy, and reviews the mechanisms, clinical manifestations, and prognostic indicators of pseudoprogression.
Article
Immunology
Ling-zhijie Kong, Ying Zheng, Kaichun Li
Summary: Treatment options for metastatic colorectal cancer are limited after second-line chemotherapy failure. In this case report, a 59-year-old male patient achieved remarkable response to fruquintinib and toripalimab combination therapy after multiple lines of chemotherapy failed. The patient had partial response within 3 months and complete response of pulmonary masses within 12 months. The combination of fruquintinib and PD-1 inhibitors improves the prognosis of metastatic colorectal cancer, with a progression-free survival of over 17 months.