Anticancer activity of novel unnatural synthetic isoprenoids.
BACKGROUND
The KRAS oncogene has a high prevalence in solid malignancies. Targeting KRAS and inappropriate activation of the MAPK pathway with novel drugs is of interest. This study developed and screened a library of compounds designed to inhibit KRAS signaling by altering prenyl function.


METHODS
To screen a library of novel farnesyl analogs for their anticancer activity in human lung cancer and breast cancer cell lines. To evaluate if the designed and actual pharmacology are congruent.


RESULTS
Sixty-seven novel compounds were tested and 70% of them screened positive for activity in at least one cell line. Two active compounds inhibited phosphorylation of MAP kinase consistent with KRAS inhibition.


CONCLUSIONS
Although 47 of the 67 novel agents screened positive for activity, none of them were highly potent. However, targeting RAS with compounds that compete with farnesyl and geranylgeranyl modification of the protein remains viable and further work is already underway to create second generation molecules.
Adams
Val R
VR
Department of Pharmacy Practice and Science, University of Kentucky, Lexington, KY 40536, USA. vadam0@email.uky.edu
Deremer
David L
DL
Stevich
Bojana
B
Mattingly
Cynthia A
CA
Gallt
Becky
B
Subramanian
Thangaiah
T
Troutman
Jerry M
JM
Spielmann
H Peter
HP
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012717:Sesquiterpenes / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
C117307:KRAS protein, human; D011106:Polyisoprenyl Phosphates; D011518:Proto-Oncogene Proteins; D012717:Sesquiterpenes; D013729:Terpenes; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins