Chemical genetic screening for compounds that preferentially inhibit growth of methylthioadenosine phosphorylase (MTAP)-deficient Saccharomyces cerevisiae.
Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, is inactivated in a variety of human cancers. Since all human tissues express MTAP, it would be of potential interest to identify compounds that selectively inhibit the growth of MTAP-deficient cells. To determine if MTAP inactivation could be targeted, the authors have performed a differential chemical genetic screen in isogenic MTAP(+) and MTAP(-) Saccharomyces cerevisiae. A low molecular weight compound library containing 30,080 unique compounds was screened for those that selectively inhibit growth of MTAP(-) yeast using a differential growth assay. One compound, containing a 1,3,4-thiadiazine ring, repeatedly showed a differential dose response, with MTAP(-) cells exhibiting a 4-fold shift in IC(50) compared to MTAP(+) cells. Several structurally related derivatives of this compound also showed enhanced growth inhibition in MTAP(-) yeast. These compounds were also examined for growth inhibition of isogenic MTAP(+) and MTAP(-) HT1080 fibrosarcoma cells, and 4 of the 5 compounds exhibited evidence of modest but significant increased potency in MTAP(-) cells. In summary, these studies show the feasibility of differential growth screening technology and have identified a novel class of compounds that can preferentially inhibit growth of MTAP(-) cells.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Yuwaraj
Y
Kadariya
Baiqing
B
Tang
Cynthia B
CB
Myers
Jami
J
Fukui
Jeffrey R
JR
Peterson
Warren D
WD
Kruger
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008715:Methionine / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D013829:Thiadiazines; D008715:Methionine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase