Names | |
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IUPAC name 3-[(Dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide | |
Other names PCI-24781; CRA-024781 | |
Identifiers | |
3D model (JSmol) | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.241.399 |
KEGG | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C21H23N3O5 | |
Molar mass | 397.431 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Abexinostat (INN, [1] formerly PCI-24781) is an experimental drug candidate for cancer treatment. [2] It was developed by Pharmacyclics and licensed to Xynomic. As of 2013 [update] , it was in Phase II clinical trials for B-cell lymphoma. [3] [ needs update ] Pre-clinical study suggests the potential for treatment of different types of cancer as well. [4] [5] [6] [7]
Abexinostat exerts its effect as a pan-histone deacetylase inhibitor [8] [9] and inhibits RAD51, which is involved in repairing DNA double strand breaks. [10]
Abexinostat has been granted a fast track designation by the FDA for the treatment of patients with relapsed or refractory follicular lymphoma in the fourth-line setting. This designation is significant as it aims to expedite the development and review of drugs intended to treat serious conditions and fill an unmet medical need.
The FORERUNNER conducted a study, a potentially pivotal phase II trial of abexinostat monotherapy in patients with relapsed/refractory follicular lymphoma, in the United States and Europe. [11] In the phase II study, abexinostat showed a modest overall response rate (ORR) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with a notably higher ORR observed in patients with follicular lymphoma. This study involved 100 patients treated with 80 mg of abexinostat twice daily for 14 days of a 21-day cycle. The ORR for follicular lymphoma specifically was 56%, indicating a significant impact on this lymphoma subtype. The study also reported grade ≥3 adverse events in a considerable number of patients, with thrombocytopenia, neutropenia, and anemia being the most frequently reported. [11]
Abexinostat has been characterized by its unique pharmacokinetic profile and oral dosing schedule, allowing for continuous exposure at concentrations required for efficient tumor cell killing. [12]
Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.
Vorinostat (rINN), also known as suberoylanilide hydroxamic acid, is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).
Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.
Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene.
Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor.
Romidepsin, sold under the brand name Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium Chromobacterium violaceum, and works by blocking enzymes known as histone deacetylases, thus inducing apoptosis. It is sometimes referred to as depsipeptide, after the class of molecules to which it belongs. Romidepsin is branded and owned by Gloucester Pharmaceuticals, a part of Celgene.
Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including follicular lymphoma, Hodgkin's lymphoma and acute myelogenous leukemia.
Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.
Quisinostat is an experimental drug candidate for the treatment of cancer. It is a "second generation" histone deacetylase inhibitor with antineoplastic activity. It is highly potent against class I and II HDACs.
Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. It was developed by Gilead Sciences. It is taken orally.
Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.
Resminostat is an orally bioavailable inhibitor of histone deacetylases (HDACs), of which inhibitors are antineoplastic agents.
Tucidinostat is a histone deacetylase inhibitor (HDI) developed in China. It was also known as HBI-8000. It is a benzamide HDI and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.
Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.
Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.
Indolent lymphoma, also known as low-grade lymphoma, is a group of slow-growing non-Hodgkin lymphomas (NHLs). Because they spread slowly, they tend to have fewer signs and symptoms when first diagnosed and may not require immediate treatment. Symptoms can include swollen but painless lymph nodes, unexplained fever, and unintended weight loss.
Zabadinostat is an experimental epigenetic drug being investigated as a potential treatment for advanced or metastatic cancers. It is an orally available Class I selective histone deacetylase (HDAC) inhibitor, with half maximal inhibitory concentrations (IC50) of 62 nM, 570 nM and 550 nM, against HDAC1, HDAC2 and HDAC3, respectively. It shows no activity against HDAC class II.
Avadomide is an experimental cereblon E3 ligase modulator, or thalidomide analog studied to see if it is effective against cancer.