chemistry

Vorinostat

Vorinostat is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Vorinostat rather than just read about it. In short: Vorinostat (INNTooltip International Nonproprietary Name), also known as suberoylanilide hydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA), 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.

Key takeaways

Vorinostat belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Vorinostat to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Vorinostat from memory before moving on to harder problems.

Reference excerpt

Vorinostat (INNTooltip International Nonproprietary Name), also known as suberoylanilide hydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA), 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. Vorinostat is marketed under the name Zolinza ( zoh-LIN-zə) by Merck for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies. The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.

Medical uses Vorinostat was the first histone deacetylase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It is taken once daily with food.

Available forms Vorinostat is available in the form of 100 mg oral capsules.

Pharmacology

Pharmacodynamics

Vorinostat has been shown to bind to the active site of histone deacetylases (HDACs) and act as a chelator for zinc ions also found in the active site of histone deacetylases. It specifically inhibits the class I HDAC1, HDAC2, and HDAC3 and the class IIb HDAC6, all with high nanomolar potency. Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.

Pharmacokinetics

Absorption The oral bioavailability of vorinostat is 1.8 to 11%. The time to peak levels (Tmax) of vorinostat varies depending on whether it is taken while fasted or with a high-fat meal. Its Tmax while fasted was median 1.5 hours (range 0.5–10 hours), whereas its Tmax with a high-fat meal was median 4 hours (range 2–10 hours). Hence, a high-fat meal delayed its Tmax by about 2.5 hours.

Distribution Vorinostat shows poor brain penetrance and only subtle brain HDAC inhibition in rodents. It is known to be a substrate for the blood–brain barrier efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP). The plasma protein binding of vorinostat is approximately 71%.

Metabolism Vorinostat is metabolized by glucuronidation and by hydrolysis followed by β-oxidation. The two major metabolites of vorinostat circulate at 4- to 13-fold higher concentrations than vorinostat itself and are pharmacologically inactive. Vorinostat is not metabolized by cytochrome P450 enzymes.

Elimination The elimination half-life of vorinostat is approximately 2 hours.

History In 1966, Charlotte Friend published her observation that a suspension of murine erythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated with dimethylsulfoxide (DMSO, a common drug solvent and cryoprotectant frequently used for cell culture freezing) at 280 mmolar. Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist Ronald Breslow about these findings and together they decided to develop more potent analogs of DMSO, in order to make use of this property for cancer treatment. Their optimization process lead to the discovery of suberoylanilide hydroxamic acid and its HDAC-inhibiting property.

Research Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL. A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies). Further brain tumor trials are planned in which vorinostat will be combined with other drugs. Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival. It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with idarubicin and cytarabine. It failed to demonstrate efficacy in treating acute myeloid leukemia in an earlier phase II study.

Preclinical research Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill". Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both in vitro and in vivo. Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency and cystic fibrosis. Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease. Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat, belinostat, and panobinostat might be repurposed to treat infections caused by human papillomavirus, or HPV.

See also Histone deacetylase inhibitor Trichostatin A

References

External links Vorinostat bound to proteins in the PDB

Worked examples

Example 1 — a first encounter with Vorinostat

Start with the simplest possible case. Write down what Vorinostat claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Vorinostat before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Vorinostat ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Vorinostat

In research: Vorinostat appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Vorinostat in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Vorinostat is common in secondary-school and first-year university syllabi. It links to neighbouring topics Anilides, Antineoplastic drugs, Drugs developed by Merck & Co., so understanding it makes those chapters shorter.
In everyday life: Look for Vorinostat outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Vorinostat in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Vorinostat means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Vorinostat out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Vorinostat in simple terms?

Why does Vorinostat matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Vorinostat?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Vorinostat.