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Taking Aim at the Undruggable
1Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract:
The term "undruggable" is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into "druggable" targets. Thus, "difficult to drug" or "yet to be drugged" are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmacologically targeting these intractable proteins is now a key challenge of modern drug development, requiring innovation and the development of new technologies. In this article, we discuss some of the recent technologic and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe recent successes in drugging the undruggable RAS (KRAS G12C and HRAS), and discuss the advances that have led to the validation of further targets previously believed to be undruggable, such as HIF-2α, BCL-2, MDM2, and MLL. Finally, we look to the future and describe important advances that are likely to have a major impact on targeting undruggable targets, such as the advent of proteolysis-targeting chimeras and protein-protein modulators, which are leading to considerable excitement surrounding the development of cancer targets.
Insights
Scientists are developing new ways to target previously "undruggable" proteins in cancer. Recent advances are making difficult-to-drug targets, like RAS, more accessible for cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- The term "undruggable" describes proteins resistant to pharmacological targeting.
- Cancer research faces challenges with elusive targets like STAT3, TP53, and MYC.
- Developing drugs for these targets is a key goal in modern drug development.
Purpose of the Study:
- To discuss recent technological and pharmacological advances eroding the concept of "undruggable" targets.
- To highlight successes in targeting previously intractable proteins in cancer.
- To explore future strategies for targeting difficult-to-drug proteins.
Main Methods:
- Review of recent technologic and pharmacologic advances.
- Discussion of successful drug development for previously undruggable targets.
- Exploration of emerging technologies like proteolysis-targeting chimeras.
Main Results:
- Erosion of the "undruggable" concept due to new technologies.
- Successful targeting of previously intractable targets such as RAS (KRAS G12C, HRAS), HIF-2α, BCL-2, MDM2, and MLL.
- Validation of new approaches for previously undruggable targets.
Conclusions:
- Significant progress has been made in targeting proteins once considered undruggable.
- Emerging technologies like proteolysis-targeting chimeras promise to revolutionize cancer target development.
- The future of cancer drug development involves innovative strategies for previously intractable targets.
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