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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,

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