2 research outputs found
Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics
Accelerated proliferation of solid tumor and hematologic
cancer cells is linked to accelerated transcription of rDNA by the
RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA
(rRNA). Indeed, upregulation of Pol I, frequently caused by mutational
alterations among tumor suppressors and oncogenes, is required for
maintenance of the cancer phenotype and forms the basis for seeking
selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5<i>H</i>-7-thia-1,11<i>b</i>-diaza-benzo[<i>c</i>]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, <b>7c</b>) has been identified as the first potent, selective, and
orally bioavailable inhibitor of RNA Pol I transcription with in vivo
activity in tumor growth efficacy models. The preclinical data support
the development of CX-5461 as an anticancer drug with potential for
activity in several types of cancer
Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
Approximately
80% of breast cancers are estrogen receptor alpha
(ER-α) positive, and although women typically initially respond
well to antihormonal therapies such as tamoxifen and aromatase inhibitors,
resistance often emerges. Although a variety of resistance mechanism
may be at play in this state, there is evidence that in many cases
the ER still plays a central role, including mutations in the ER leading
to constitutively active receptor. Fulvestrant is a steroid-based,
selective estrogen receptor degrader (SERD) that both antagonizes
and degrades ER-α and is active in patients who have progressed
on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical
properties and must be administered by intramuscular injections that
limit the total amount of drug that can be administered and hence
lead to the potential for incomplete receptor blockade. We describe
the identification and characterization of a series of small-molecule,
orally bioavailable SERDs which are potent antagonists and degraders
of ER-α and in which the ER-α degrading properties were
prospectively optimized. The lead compound <b>11l</b> (GDC-0810
or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive
and tamoxifen-resistant breast cancer, and is currently in clinical
trials in women with locally advanced or metastatic estrogen receptor-positive
breast cancer