Jerome Horwitz designed 'fraudulent' DNA building blocks

Person

Jerome Horwitz

Lived

1919–2012

Field

Medicinal chemistry

From

American

The story

In the early 1960s much cancer drug research involved pulling chemicals off the shelf almost at random to see whether any slowed tumours in mice. Jerome Horwitz, a Detroit-born chemist at the Detroit Institute of Cancer Research and Wayne State University, found that approach intellectually unsatisfying. He wanted to design a drug aimed squarely at what made cancer cells grow.

He reasoned instead from biology. Cancer cells divide constantly, and to divide they must copy their DNA, which is built from units called nucleosides. Horwitz set out to make what he called fraudulent nucleosides, molecules so similar to the real thing that a cell would be tricked into using them, but altered so that once built into a growing DNA chain they would halt it.

Over the next few years his laboratory produced a family of these impostors. AZT came in 1964. Stavudine, then called d4T, was first described in 1966, and dideoxycytidine, or ddC, followed around 1967. When AZT was tested in mice with leukaemia it had no effect, and Horwitz eventually set it aside without seeking a patent.

A long-time colleague, Wei-Zen Wei, an associate director at the Karmanos Cancer Institute, said he had devoted his life to designing a therapy that would strike at the heart of the disease, and that he took a chance in doing so. His method of building a drug around a specific biological target, rather than finding one by trial and error, is today called rational drug design.

The compounds failed against cancer, but the principle found its target two decades later. HIV copies its genetic material with an enzyme called reverse transcriptase, and the enzyme readily takes up Horwitz's fakes, ending each chain it starts. AZT was approved against HIV in 1987, ddC in 1992 and stavudine in 1994. Drugs of this class, known as nucleoside reverse transcriptase inhibitors, remain a core part of the combination therapy that keeps people with HIV healthy today.

Why it matters

Horwitz's idea of designing molecules to block genetic copying underlies drugs that have kept millions of people with HIV alive, and it helped show the power of designing medicines around a known biological target.

About Jerome Horwitz

Detroit chemist who made AZT in 1964 as a cancer drug that failed, two decades later it became the first approved treatment for HIV/AIDS, though he never earned a cent from it.

More about Jerome Horwitz

• Jerome Horwitz made AZT, the first HIV treatmentIn 1964 Detroit chemist Jerome Horwitz synthesised AZT as a possible cancer drug; in 1987 it became the first approved treatment for HIV, and he also first made two more HIV drugs.
• Jerome Horwitz fought cancer in the lab until 86Jerome Horwitz kept working on cancer drugs into his eighties, sharing a $900,000 NCI grant for solid-tumour drugs and retiring from Wayne State in 2005 at 86.
• Horwitz's ddC became one of the first HIV drugsDideoxycytidine (ddC), first made in Jerome Horwitz's lab in the 1960s, was approved by the FDA in 1992 as one of the earliest HIV/AIDS treatments.
• Horwitz's stavudine treated HIV in poorer countriesStavudine (d4T), first created by Jerome Horwitz in the 1960s, was approved for HIV in 1994 and became widely used in developing countries for its low cost.
• Jerome Horwitz made X-gal, a staple of genetics labsIn 1964 Jerome Horwitz and colleagues first made X-gal, the compound that turns bacteria blue and lets biologists spot engineered DNA at a glance.

Sources

• Billions from drug bypassed creator InvestSmart (obituary reprint)
• AIDS drug AZT inventor and famed cancer scientist Jerome Horwitz dies at 93 Wayne State University

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