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Computational Drug Discovery and Development Along With Their Applications in the Treatment of Women-Associated Cancers
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
Rahul Kumar, Rakesh Kumar, Harsh Goel, Somorjit Singh Ningombam, Pranay Tanwar
Target deconvolution is the retrospective approach based on the observed phenotypic response [15]. This method shows its promising effect in cancer because of its complexity and gain importance in the discovery of biological target. Panobinostat is one such example which is used to inhibit the activity of HDACs that is involve in the regulation of gene expression. Currently, by harnessing its therapeutic treatment in BC, panobinostat along with other antineoplastic agents and nucleoside metabolic inhibitors ended in a phase 1/2 clinical trial (NCT00632489) [16].
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The HDAC inhibitor panobinostat (FarydakTM), developed by Novartis, is a hydroxamic acid derivative and acts as a nonselective (i.e., pan) HDAC inhibitor, leading to the apoptosis of malignant cells via multiple pathways. Given orally, it is the only HDAC inhibitor recommended by NICE for use in the UK for the treatment of relapsed or refractory multiple myeloma (in combination with bortezomib and dexamethasone). Panobinostat received FDA-accelerated approval for use in patients with multiple myeloma in 2015 and was approved for the same use by the EMA in 2015. Common side effects in >10% of patients include low blood cell counts (i.e., pancytopenia, thrombocytopenia, anemia, leucopenia, neutropenia, and lymphopenia), airway infections, fatigue, diarrhea, nausea, headache, and sleeping problems.
Diffuse Intrinsic Pontine Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Katherine E. Warren, Carolyn R. Freeman, Dannis G. van Vuurden
Given the frequency of histone mutations in the majority of patients with DIPG, there is a strong rationale to investigate treatments with histone deacetylase inhibitors. HDAC inhibitors (HDACi) have been shown to induce differentiation, cell cycle arrest, or apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal models.86–88 Panobinostat is a potent pan-HDAC inhibitor of class I, II, and IV HDACs, that induces expression of cell cycle control genes and selectively inhibits the proliferation of a variety of tumor cells compared to normal cells. It has been extensively profiled for its in vitro and in vivo pharmacological activity on a variety of tumor cell lines and tumor xenograft mice models.89 In a chemical screen against 16 patient-derived DIPG cell cultures, panobinostat was identified as one of the most effective agents, with activity demonstrated in 12 of the 16 cell cultures.90 Antitumor activity of panobinostat was also observed in vivo utilizing DIPG orthotopic models, with panobinostat administered intratumorally by CED as well as via systemic administration.90 A phase I trial of orally administered panobinostat to children with DIPG is currently under way. Additionally, panobinostat administered via CED is under preclinical investigation.91
An update on the emerging approaches for histone deacetylase (HDAC) inhibitor drug discovery and future perspectives
Published in Expert Opinion on Drug Discovery, 2021
Along with further research on HDACs, HDAC inhibitors have attracted many attentions in recent decades. So far there have been more than 30 HDAC inhibitors investigated in clinic trials and have achieved five approvals (Figure 1)[24]. Vorinostat (compound 1) is the first FDA-approved HDAC inhibitor in 2006 to treat cutaneous T-cell lymphoma[25]. In 2009, Romidepsin (compound 2) was received FDA approval as cutaneous T-cell lymphoma treatment as well. In 2014, Belinostat (compound 3) is the third HDAC inhibitor to receive FDA approval for T-cell lymphoma treatment[26]. Panobinostat (compound 4) received approval by both the FDA and the EMA to treat relapsed or refractory multiple myeloma[27]. Lastly, in 2015, Tucidinostat (compound 5) was approved by the CFDA as treatment of peripheral T-cell lymphoma.
A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies
Published in Pediatric Hematology and Oncology, 2020
John Goldberg, Maria Luisa Sulis, Julia Bender, Sima Jeha, Rebecca Gardner, Jessica Pollard, Victor Aquino, Theodore Laetsch, Naomi Winick, Cecilia Fu, Leigh Marcus, Weili Sun, Anupam Verma, Michael Burke, Phoenix Ho, Thomas Manley, Rajen Mody, Wendy Tcheng, Blythe Thomson, Julie Park, Richard Sposto, Yoav Messinger, Nobuko Hijiya, Paul Gaynon, Julio Barredo
In 2015, panobinostat was approved by the FDA for the treatment of multiple myeloma in combination with bortezomib and dexamethasone for patients who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent. Notably, a Risk Evaluation and Management Strategy (REMS) was required for panobinostat due to cardiac toxicity and diarrhea – up to 25% of adults exposed to panobinostat had severe diarrhea and patients who received the drug experienced diarrhea more frequently than those who did not. Additionally, adults treated with panobinostat had an increased risk for cardiac events, including arrhythmias that may have been exacerbated by electrolyte abnormalities. 14 Panobinostat was also approved by the EMA for the same indication, with similar acknowledgement of safety concerns. 15
Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia
Published in Expert Opinion on Emerging Drugs, 2018
Simon Kavanagh, Aisling Nee, Jeffrey H. Lipton
Panobinostat (LBH589) is a potent inhibitor of HDAC enzymes, promoting histone acetylation and influencing gene expression within malignant cells. Panobinostat is also likely to influence acetylation of certain proteins, with treatment in CML models favoring acetylation of Hsp90. Hsp90 acetylation impairs its chaperone function, increasing proteasomal degradation of important signaling proteins [84]. Single-agent panobinostat has been shown to inhibit growth of multiple CML cell lines, including one with the T315I mutation [85]. Mechanistic studies support the degradation of BCR-ABL protein and consequent suppression of downstream signaling as the mode of action. Furthermore, synergistic induction of apoptosis and signaling inhibition was observed with coadministration of ponatinib.