TY - JOUR
T1 - Structural and computational perspectives of selectively targeting mutant proteins
AU - Coban, Mathew A.
AU - Fraga, Sarah
AU - Caulfield, Thomas R.
N1 - Publisher Copyright:
© 2021 Bentham Science Publishers.
PY - 2021
Y1 - 2021
N2 - Diseases are often caused by mutant proteins. Many drugs have limited effectiveness and/or toxic side effects because of a failure to selectively target the disease-causing mutant variant, rather than the functional wild type protein. Otherwise, the drugs may even target different proteins with similar structural features. Designing drugs that successfully target mutant proteins selectively represents a major challenge. Decades of cancer research have led to an abundance of potential therapeutic targets, often touted to be “master regulators”. For many of these proteins, there are no FDA-approved drugs available; for others, off-target effects result in dose-limiting toxicity. Cancer-related proteins are an excellent medium to carry the story of mutant-specific targeting, as the disease is both initiated and sustained by mutant proteins; furthermore, current chemotherapies generally fail at adequate selective distinction. This review discusses some of the challenges associated with selective targeting from a structural biology perspective, as well as some of the developments in algorithm approach and computational workflow that can be applied to address those issues. One of the most widely researched proteins in cancer biology is p53, a tumor sup-pressor. Here, p53 is discussed as a specific example of a challenging target, with contemporary drugs and methodologies used as examples of burgeoning successes. The oncogene KRAS, which has been described as “undruggable”, is another extensively investigated protein in cancer biology. This review also examines KRAS to exemplify progress made towards selective targeting of disease-causing mutant proteins. Finally, possible future directions relevant to the topic are discussed.
AB - Diseases are often caused by mutant proteins. Many drugs have limited effectiveness and/or toxic side effects because of a failure to selectively target the disease-causing mutant variant, rather than the functional wild type protein. Otherwise, the drugs may even target different proteins with similar structural features. Designing drugs that successfully target mutant proteins selectively represents a major challenge. Decades of cancer research have led to an abundance of potential therapeutic targets, often touted to be “master regulators”. For many of these proteins, there are no FDA-approved drugs available; for others, off-target effects result in dose-limiting toxicity. Cancer-related proteins are an excellent medium to carry the story of mutant-specific targeting, as the disease is both initiated and sustained by mutant proteins; furthermore, current chemotherapies generally fail at adequate selective distinction. This review discusses some of the challenges associated with selective targeting from a structural biology perspective, as well as some of the developments in algorithm approach and computational workflow that can be applied to address those issues. One of the most widely researched proteins in cancer biology is p53, a tumor sup-pressor. Here, p53 is discussed as a specific example of a challenging target, with contemporary drugs and methodologies used as examples of burgeoning successes. The oncogene KRAS, which has been described as “undruggable”, is another extensively investigated protein in cancer biology. This review also examines KRAS to exemplify progress made towards selective targeting of disease-causing mutant proteins. Finally, possible future directions relevant to the topic are discussed.
KW - KRAS
KW - Mutant proteins
KW - Oncogene
KW - Oncogenic mutant
KW - P53
KW - Selective targeting
UR - http://www.scopus.com/inward/record.url?scp=85107656041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107656041&partnerID=8YFLogxK
U2 - 10.2174/1570163817666200311114819
DO - 10.2174/1570163817666200311114819
M3 - Article
C2 - 32160847
AN - SCOPUS:85107656041
SN - 1570-1638
VL - 18
SP - 365
EP - 378
JO - Current Drug Discovery Technologies
JF - Current Drug Discovery Technologies
IS - 3
ER -