Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.
Histone H3-lysine79 (H3K79) methyl transferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure and mechanism based design to discover several potent inhibitors of DOT1L with IC50 values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The x-ray crystal structure of a DOT1L:inhibitor complex reveals that N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.
Expression of a bacterial transporter protein in Toxoplasma gondii results in parasite susceptibility to Formidomycin, a drug targeting isoprenoid precursor synthesis.
Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with Ki values as low as 0.5 nM. These compounds also show high selectivity (>4,500-fold) over three other histone methyltransferases. Structure activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC50 values of 4–11 μM. Isothermal titration calorimetry studies showed two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex, and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine), but not the substrate nucleosome.
Histone H3 lysine79 (H3K79) methyltransferase DOT1L plays an important role in the activation and maintenance of gene transcription. It is essential for embryonic development as well as normal functions of the hematopoietic system, heart and kidney in adults. DOT1L has been found to be a drug target for acute leukemia with mixed lineage leukemia (MLL) gene translocations. The rearranged onco-MLL can recruit DOT1L, causing aberrant H3K79 methylation, overexpression of leukemia relevant genes, and eventually leukemogenesis. Potent DOT1L inhibitors possess selective activity against this type of leukemia in cell-based and animal studies, with the most advanced compound being in clinical trials. In the medicinal chemistry point of view, we review the biochemistry, cancer biology and current inhibitors of DOT1L, as well as biophysical (including X-ray crystallographic) investigation of DOT1L-inhibitor interactions. Potential future directions in the context of drug discovery and development targeting DOT1L are discussed.
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