11:12 AM
Dec 15, 2016
 |  BC Innovations  |  Product R&D

p53 and Ras: Back from the dead

Why drug developers haven't given up on p53 and Ras

After decades of research and countless failed attempts at drug development, industry is reviving its interest in two of oncology’s most intractable targets, p53 and Ras. While no one denies there’s still a long road ahead, glimmers of enthusiasm are emerging around the small crop of newcos that believe they’ve found solutions.

For p53, the answers lie in advances in computational chemistry and biology that enabled structure-based drug design with precision that was previously not possible. For Ras, new therapeutic modalities are enabling drug developers to address areas afresh where small molecules ran aground.

Although p53 and Ras were hailed as some of the most important players in cancer over 30 years ago, little progress has been made in drug development for either one. There are no marketed products targeting either protein, and only a handful of compounds has made it to the clinic.

According to Brad Loncar of the Loncar Fund, the outcome thus far has been a big disappointment to the field. “For p53 and Ras, the volume of research and the number of approaches and angles people have used to try to target them is quite staggering, but nothing has gotten us into the vicinity where we would hope to be.”

The two targets are among the most commonly mutated proteins in cancer, which presents both opportunities and drawbacks. p53 is mutated in over 50% of all human cancers, more than any other single target. Members of the Ras family of proteins - KRAS, NRAS and HRAS - are mutated in about 30% of all human cancers, including some of the most aggressive tumors, such as lung and pancreatic cancers.

“Both of these targets are so important because they are ubiquitously expressed in cancers, but just because it’s ubiquitously expressed doesn’t mean it’s a good target. In fact, it is usually the opposite,” said Loncar.

While p53 and Ras have distinct properties that create problems for drug developers, both have multiple mutants and feed into a range of complex cellular processes that make them simultaneously attractive and difficult to pursue.

According to Arnold Levine, who discovered p53 in 1979, that complexity has caused industry to avoid them, taking instead the path of least resistance by targeting proteins that offer a faster path to market. Levine is a professor emeritus at the Institute for Advanced Study.

Levine told BioCentury companies have ended up pursuing less common cancer mutations “not because they make a big impact on cancer, but because they’re easy to target.”

For example, protein tyrosine kinases are each infrequently mutated in cancers, yet they’ve all been targeted because “we know how to make inhibitors,” he said. “In contrast, the handful of more common mutations would have a much bigger impact on cancer, but aren’t easy to hit.”

Now, at least 12 companies are finding new ways to drug the difficult targets, taking advantage of biological advances that have either increased knowledge around the proteins, generated new technologies or provided new therapeutic modalities (see “Ras and p53 Technologies”).

Table: Ras and p53 technologies

Select technologies being employed to develop drugs against the challenging targets Ras and p53. At least seven companies are developing therapeutics or drug platforms to inhibit Ras isoforms using a variety of therapeutic modalities. While five of the programs are specifically targeting oncogenic K-Ras (KRAS), which is the most frequently mutated isoform in cancers, one is targeting v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) and another is targeting unspecified Ras mutants. At least four other companies are targeting the tumor suppressor p53, including two companies developing structural correctors designed to restore protein function. Source: BCIQ: BioCentury Online Intelligence; company websites

TargetModalityCompanies/InstitutionsTechnology descriptionPhase of development
p53Gene therapyMultiVir...

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