Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.

Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC50 = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC50 = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme.

Retention of Vaginal Breech Delivery Skills Taught in Simulation.

OBJECTIVE: The optimal frequency of conducting simulation training for high-acuity, low-frequency events in obstetrics and gynaecology residency programs is unknown. This study evaluated retention over time of vaginal breech delivery skills taught in simulation, by comparing junior and senior residents. In addition, the residents' subjective comfort level to perform this skill clinically was assessed. METHODS: This prospective cohort study included 22 obstetrics and gynaecology residents in a Canadian residency training program. Digital recordings were completed for pre-training, immediate post-training, and delayed (10-26 weeks later) post-training intervals of a vaginal breech delivery simulation, with skill assessment by a blinded observer using a binary checklist. Residents also completed questionnaires to assess their subjective comfort level at each interval. RESULTS: Junior and senior residents had significant improvements in vaginal breech delivery skills from the pre-training assessment to both the immediate post-training assessment (junior, P <0.001; senior, P <0.001) and the delayed post-training assessment (P <0.001 and P = 0.001, respectively). There was a significant decline in skills between the immediate and delayed post-training sessions for junior and senior residents (P = 0.003 and P <0.001, respectively). Both junior and senior residents gained more comfort immediately after the training (P <0.001 and P <0.001, respectively), without a significant change between immediate post-training and delayed post-training comfort levels (P = 0.19 and P = 0.11, respectively). CONCLUSION: Residents retained vaginal breech delivery skills taught in simulation 10-26 weeks later, although a decline in skills occurred over this time period. Comfort level was positively affected and retained. These results will aid in determining the frequency of simulation teaching for high-acuity, low-frequency events in a residency simulation curriculum.

Discovery and Preclinical Evaluation of BMS-986242, a Potent, Selective Inhibitor of Indoleamine-2,3-dioxygenase 1.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing dioxygenase enzyme implicated in cancer immune response. This account details the discovery of BMS-986242, a novel IDO1 inhibitor designed for the treatment of a variety of cancers including metastatic melanoma and renal cell carcinoma. Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.

Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors.

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

The self-inflating resuscitation bag delivers high oxygen concentrations when used without a reservoir: implications for neonatal resuscitation.

OBJECTIVE: To measure the delivered fractional oxygen concentration (F(DO(2))) from preterm-size Laerdal silicone resuscitators (PLSR) without a reservoir. BACKGROUND: The North American Neonatal Resuscitation Program manual states that self-inflating bags without a reservoir deliver approximately 40% oxygen, differing from the PLSR manufacturer's specifications. METHODS: A neonatal test lung was manually ventilated using PLSRs without a reservoir. A 50 psi 100% oxygen source and an oxygen flow meter were used to provide desired oxygen inlet flows. F(DO(2)) was measured using 3 different PLSRs after 4 min of manual ventilation of a neonatal test lung, at differing inspired tidal volumes (5 mL or 20 mL), respiratory rates (40 breaths/min or 60 breaths/min), and oxygen inlet flows (1 to 4, 5, and 10 L/min). RESULTS: In all tests using 5 or 10 L/min, exceeded 0.95. The lowest F(DO(2)) was 0.59, at 1 L/min. CONCLUSIONS: The F(DO(2)) measured during this study did not differ from PLSR specifications. The F(DO(2)) did, however, differ from information contained in the North American Neonatal Resuscitation Program manual regarding use of a self-inflating bag without a reservoir. Care should be taken when selecting a self-inflating resuscitation device to provide blended air and oxygen, as high concentrations of oxygen may be delivered by these devices even when the reservoir is removed. American and Canadian recommendations for the provision of supplemental oxygen with self-inflating bags require reevaluation.

Antroquinonol A: Scalable Synthesis and Preclinical Biology of a Phase 2 Drug Candidate.

The fungal-derived Taiwanese natural product antroquinonol A has attracted both academic and commercial interest due to its reported exciting biological properties. This reduced quinone is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC) and was recently granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Pending successful completion of human clinical trials, antroquinonol is expected to be commercialized under the trade name Hocena. A synthesis-enabled biological re-examination of this promising natural product, however, reveals minimal in vitro and in vivo antitumor activity in preclinical models.

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression.

The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.

Synthesis and Biological Evaluation of 1-Deoxypaclitaxel Analogues.

The naturally occurring taxoid baccatin VI has been converted to various 1-deoxypaclitaxel derivatives by selective deacylation followed by attachment of the C-13 side chain. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with activity comparable to that of paclitaxel were discovered. It thus appears that the 1-hydroxyl group is not necessary for the activity of paclitaxel.

Assessment of benefit in tele-ophthalmology using a consensus panel.

A videoconferencing link was established from a hospital in South Africa to Moorfields Eye Hospital in London. A clinician in South Africa used a video slit-lamp and videoconferencing equipment to capture images and communicate with a specialist in London. Over 12 months, 113 cases were discussed in teleconsultations. Case-notes were subsequently obtained for 90 cases (80%). Three consultant ophthalmologists took part in the consensus process, one from the UK and two from South Africa. The consensus panel achieved on average 78-96% agreement on the items rated. In approximately half the cases, the panel judged that teleconsultation had had an effect on diagnosis. In nine cases (10%) there was potential for definite improvement in visual health as a result of tele-ophthalmology and in a further 48 cases (53%) there was potential for possible improvement in visual health. The consensus process identified 35 cases (39%) where there was potential improvement in general health as a result of tele-ophthalmology. Despite the methodological limitations of our approach, it was possible to learn a great deal about the effectiveness of the telemedicine intervention.

Preclinical efficacy spectrum and pharmacokinetics of ixabepilone.

PURPOSE: Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes the pharmacokinetics of this new antineoplastic agent. METHODS: The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in vivo in human xenografts in mice. Antitumor activities of ixabepilone and taxanes were compared in multidrug-resistant models in vivo. Differential drug uptake of ixabepilone and paclitaxel was assessed in a P-glycoprotein (P-gp)-resistant colon cancer model in vitro. The pharmacokinetic profile of ixabepilone was established in mice and humans. RESULTS: Ixabepilone demonstrated potent cytotoxicity in a broad range of human cancer cell lines in vitro and in a wide range of xenografts in vivo. Ixabepilone was *3-fold more potent than docetaxel in the paclitaxel-resistant Pat-21 xenograft model (resistant due to overexpression of betaIII-tubulin and a lack of betaII-tubulin). Ixabepilone activity against P-gp-overexpressing breast and colon cancer was confirmed in in vivo models. Cellular uptake of ixabepilone, but not paclitaxel, was established in a P-gp-overexpressing model. The pharmacokinetics of ixabepilone was characterized by rapid tissue distribution and extensive tissue binding. CONCLUSIONS: Cytotoxicity studies against a range of tumor types in vitro and in vivo demonstrate that ixabepilone has potent and broad-spectrum antineoplastic activity. This is accompanied by favorable pharmacokinetics. Ixabepilone has reduced susceptibility to resistance due to P-gp overexpression, tubulin mutations, and alterations in beta-tubulin isotype expression.