A solitary brain metastasis as the only site of recurrence of HR positive, HER2 negative breast cancer: a case report and review of the literature.

Background: Breast cancer is one of the most common causes of brain metastases. However, the presence of isolated central nervous system (CNS) metastatic disease early in the course of disease relapse is a rare event in cases of hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.

Case Presentation: We summarize the clinical course of a pre-menopausal, 39-year old Caucasian female with history of operable, hormone receptor positive, HER2 negative breast cancer who was initially treated with curative-intend therapy but who unfortunately developed solitary metastatic lesion in the left thalamus.

Remarkable response to a novel ATR inhibitor in a patient with poorly differentiated neuroendocrine carcinoma.

M6620 (formerly known as VX-970) is a potent inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a serine/threonine-specific protein kinase involved in activation of checkpoint signaling and promotion of cell cycle arrest in response to DNA damage (inhibition constant [Ki] <300 pM, IC50 of 20 nM). ATR inhibition enhances the cytotoxic effect of DNA damaging drugs and infrared radiation (IR) in many cancer cell lines and primary human tumors. M6620 is currently under investigation in early-phase clinical trials for the treatment of a number of malignancies.

Fyn is downstream of the HGF/MET signaling axis and affects cellular shape and tropism in PC3 cells.

Purpose: Fyn is a member of the Src family of kinases that we have previously shown to be overexpressed in prostate cancer. This study defines the biological impact of Fyn inhibition in cancer using a PC3 prostate cancer model.

Experimental Design: Fyn expression was suppressed in PC3 cells using an shRNA against Fyn (PC3/FYN-).

Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase.

The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.

Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy.

Discovery of triazolinone non-nucleoside inhibitors of HIV reverse transcriptase.

Novel non-nucleoside inhibitors of HIV-RT that contain pyridazinone isosteres were prepared, and a series of triazolinones were found to be potent inhibitors of HIV replication. These compounds were active against several NNRTI-resistant virus strains. Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats.

Toward a new genetic system with expanded dimensions: size-expanded analogues of deoxyadenosine and thymidine.

We describe the design, preparation, and properties of two key building blocks of a size-expanded genetic system. Nucleoside analogues of the natural nucleosides dA and dT are reported in which the fusion of a benzo ring increases their size by ca. 2.

A four-base paired genetic helix with expanded size.

We describe a new molecular class of genetic-pairing system that has a native DNA backbone but has all four base pairs replaced by new, larger pairs. The base pairs include size-expanded analogs of thymine and of adenine, both extended by the width of a benzene ring (2.4 A).