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Newly published novel small molecules and their utilities

Oct 24,2014 02:44  |  news

·       Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.  Stefan Peukert, et al. (2014) ACS Med. Chem. Lett. In press.

·       Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Bassilana F, et al. (2014) Nat Chem Biol. 10(5):343-9.

GPR39 signaling is implicated in cellular processes such as insulin secretion, protection from cell death, gastric emptying, and epithelial repair. GPR39 functions in a β-cell protective manner and it could be a target for antidiabetic drug treatment with long-term benefits. GPR39-C3 is the first potent, selective and orally bioavailable GPR39 agonist with an EC50 ~0.8 nM for human GPR39 and ~0.4 nM for rodent GPR39. It has no inhibitory effects (at 10 μM) on a panel of kinases and exhibits no relevant binding affinity for the related ghrelin and neurotensin-1 receptors and other enzymes, transporters, and GPCRs. GPR39-C3 has excellent functional activity in physiologically relevant rodent cells and in vivo. An acute study in normal mice with orally administrated GPR39-C3 confirmed in vitro findings by demonstrating an increase of the relevant pharmacodynamic marker GLP-1. It is a good chemical tool to enable interrogation of GPR39 signaling in different cellular contexts.

·       Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Kwiatkowski N, et al. (2014) Nature. 511(7511):616-20.

THZ1 is a novel potent, selective and cell permeable irreversible CDK7 inhibitor. It has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. It strongly reduces the proliferation and cell viability of T-ALL cell lines. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry in these tumor cells. THZ1 exhibited efficacy in a bioluminescent xenografted mouse model using the human T-ALL cell line KOPTK1. Pharmacological modulation of CDK7 kinase activity by using THZ1 may thus provide an approach to identify and treat tumor types that are dependent on transcription for maintenance of the oncogenic state.


·       MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Gad H, et al. (2014) Nature. 508(7495):215-21.

·       Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Huber KV, et al. (2014) Nature. 508(7495):222-7.

Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. TH588 and SCH51344 are novel potent, selective and cell permeable MTH1 inhibitors.  They have excellent selectivity over other nudix family proteins and kinases present in the selectivity panel. MTH1 inhibition by TH588 causes incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. SCH51344 inhibits Ras-induced malignant transformation and has no effect on Ras-induced ERK and JNK activation. TH588 and SCH51344 are good chemical tools to exemplify the non-oncogene addiction concept for anticancer treatment and validate MTH1 as a drug target.