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Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18), which is the most potent inhibitor (IC50=310 nm) of the UCH-2 chordoma cell line to date.

Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP’s active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = –0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.

Heteroatom rich 1,2,3-dithiazoles are relatively underexplored in medicinal chemistry. We now report screening data on a series of structurally diverse 1,2,3-dithiazoles and electronically related 1,2,4-dithiazines with the aim of identifying interesting starting points for potential future optimisation. The 1,2,3-dithiazoles, were obtained via a number of different syntheses and screened on a series of cancer cell lines. These included breast, bladder, prostate, pancreatic, chordoma and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. Several low single digit micromolar compounds with promising therapeutic windows were identified for breast, bladder and prostate cancer. Furthermore, key structural features of 1,2,3-dithiazoles are discussed, that show encouraging scope for future refinement.

Maraviroc-based regimens have been explored as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). In this study, we utilized mucosal tissue drug exposure data, combined with target concentrations generated in vitro, in a pharmacokinetic-pharmacodynamic analysis to predict the effects of drug combinations and adherence on PrEP efficacy. Mucosal tissue concentrations of maraviroc were measured in 24 healthy women. The 90% effective concentrations (EC(90)) of maraviroc (alone and combined with tenofovir and emtricitabine) for protection against HIV were identified in CD4(+) T cells. Monte Carlo simulations were performed to identify dosing strategies to protect colorectal and female genital tract (FGT) tissues from HIV infection. Colorectal maraviroc concentrations were 350-fold higher than in the FGT. Under steady-state conditions, our model predicted that one 300-mg dose/week was sufficient to protect colorectal tissue from HIV in 99% of the population, while 300 mg daily would protect the FGT in only 63% of the population. FGT protection increased to >90% when maraviroc was used in combination with tenofovir (5 doses/week) or emtricitabine (3 doses/week). Poor adherence resulted in a drastic decrease in efficacy in the FGT but not colorectal tissue. However, greater forgiveness was seen when maraviroc was combined with tenofovir or emtricitabine, suggesting that maraviroc should not be used alone as PrEP.

Epidermal growth factor receptor (EGFR) inhibitors have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We have probed several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. The EGFR target engagement was then evaluated in an in-cell assay. Additionally, inhibitors were profiled in representative cellular models of NSCLC and chordomas. In addition to a structure activity relationship insights for EGFR inhibtior design, we also identified a compound (18) that is the most potent inhibitor (IC50 = 310 nM) on the UCH-2 chordoma cell line to date.

Purpose: Metastatic urothelial bladder cancer (mUC) is incurable, and options are limited after patients fail 1st and 2nd line treatments. Thus, there is an unmet need to develop novel therapeutic strategies that increase survival in mUC patients. According to data from The Cancer Genome Atlas, UC has the third highest rate of somatic mutations, and mutations in DNA damage repair (DDR) genes are common. This provides rationale for the use of PARP inhibitors in UC patients with DDR mutations. Epigenetic changes are also common in UC, so epigenetic regulator inhibitors in combination with PARP inhibitors could be a viable treatment strategy in mUC. The purpose of this study was to evaluate the effects of combined olaparib plus an epigenetic regulator inhibitor in preclinical models of UC. Methods: BRCA1-competent 5637 cells and BRCA1-mutant J82 cells were screened against 62 compounds in the UNC EpiG Diamond library to identify epigenetic regulator inhibitors that could have synergy with olaparib. Cells were treated with 5 ascending concentrations of each compound (10 nM–10 µM), and cell viability was measured by alamarBlue™. RT-qPCR and western blotting were used to evaluate the effects of birabresib (OTX-015) on MYC and BRCA1 gene and c-MYC and BRCA1 protein expression, respectively. To evaluate birabresib effects on cell cycle, flow cytometry was performed. To evaluate cell viability, cells were treated with 8 ascending concentrations of olaparib and birabresib (0.1nM–100uM), alone and in combination, and then treated with CellTitrGlo™. IC50 values were calculated using a four-parameter non-linear regression model, and synergy estimates were derived by Compusyn software. Results: The EpiG screen revealed that as a class BET inhibitors potently limited cell viability in 5637 and J82 cells. Birabresib was particularly potent (IC50 in 5637 cells=100nM and in J82 cells=330nM; n=2), and selected for further evaluation. After 24h, birabresib significantly inhibited both MYC and BRCA1 expression (P Conclusion: Birabresib represses MYC/c-MYC and BRCA1/BRCA1 expression. Olaparib plus birabresib induces cell cycle arrest, and appears to be synergistic. This provides rationale supporting additional lines of prospective inquiry to evaluate olaparib plus birabresib in UC. Citation Format: Kaitlyn A. Maffuid, Chad D. Torrice, Brian Hardy, William A. Murphy, Lindsey I. James, William Y. Kim, Stephen V. Frye, Kenneth J. Pearce, Daniel J. Crona. Evaluation of the effects of combined chemical inhibition of PARP and BET proteins in preclinical models of urothelial bladder cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1743.

Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS-therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PKPD) such as lack of efficacy or improper selection of initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PKPD from animal models as well as choose the appropriate dose. In this review, we summarize available literature from human studies on the pharmacokinetics and pharmacodynamics in brain tissue, cerebrospinal fluid and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer’s disease and neuro-HIV and address critical questions in the field. We also explore newer methods to characterize pharmacokinetic/pharmacodynamic relationships that may lead to more efficient dose selection in CNS drug development.