Systematic analysis of electronic barrier heights and widths for concerted proton transfer in cyclic hydrogen bonded clusters: (HF)n, (HCl)n and (H2O)n where n = 3, 4, 5.

The MP2 and CCSD(T) methods are paired with correlation consistent basis sets as large as aug-cc-pVQZ to optimize the structures of the cyclic minima for (HF)n, (HCl)n and (H2O)n where n = 3-5, as well as the corresponding transition states (TSs) for concerted proton transfer (CPT). MP2 and CCSD(T) harmonic vibrational frequencies confirm the nature of each minimum and TS. Both conventional and explicitly correlated CCSD(T) computations are employed to assess the electronic dissociation energies and barrier heights for CPT near the complete basis (CBS) limit for all 9 clusters. Results for (HF)n are consistent with prior studies identifying Cnh and Dnh point group symmetry for the minima and TSs, respectively. Our computations also confirm that CPT proceeds through Cs TS structures for the C1 minima of (H2O)3 and (H2O)5, whereas the process goes through a TS with D2d symmetry for the S4 global minimum of (H2O)4. This work corroborates earlier findings that the minima for (HCl)3, (HCl)4 and (HCl)5 have C3h, S4 and C1 point group symmetry, respectively, and that the Cnh structures are not minima for n = 4 and 5. Moreover, our computations show the TSs for CPT in (HCl)3, (HCl)4 and (HCl)5 have D3h, D2d, and C2 point group symmetry, respectively. At the CCSD(T) CBS limit, (HF)4 and (HF)5 have the smallest electronic barrier heights for CPT (≈15 kcal mol-1 for both), followed by the HF trimer (≈21 kcal mol-1). The barriers are appreciably higher for the other clusters (around 27 kcal mol-1 for (H2O)4 and (HCl)3; roughly 30 kcal mol-1 for (H2O)3, (H2O)5 and (HCl)4; up to 38 kcal mol-1 for (HCl)5). At the CBS limit, MP2 significantly underestimates the CCSD(T) barrier heights (e.g., by ca. 2, 4 and 7 kcal mol-1 for the pentamers of HF, H2O and HCl, respectively), whereas CCSD overestimates these barriers by roughly the same magnitude. Scaling the barrier heights and dissociation energies by the number of fragments in the cluster reveals strong linear relationships between the two quantities and with the magnitudes of the imaginary vibrational frequency for the TSs.

Precision Population Cancer Medicine in Cancer of the Uterine Cervix: A Potential Roadmap to Eradicate Cervical Cancer.

With the success of the Human Genome Project, the era of genomic medicine (GM) was born. Later on, as GM made progress, there was a feeling of exhilaration that GM could help resolve many disease processes. It also led to the conviction that personalized medicine was possible, and a relatively synonymous word, precision medicine (PM), was coined. However, the influence of environmental factors and social determinants of diseases was only partially given their due importance in the definition of PM, although more recently, this has been recognized. With the rapid advances in GM, big data, data mining, wearable devices for health monitoring, telemedicine, etc., PM can be more easily extended to population-level health care in disease management, prevention, early screening, and so on.and the term precision population medicine (PPM) more aptly describes it. PPM's potential in cancer care was posited earlier,and the current authors planned a series of cancer disease-specific follow-up articles. These papers are mainly aimed at helping emerging students in health sciences (medicine, pharmacy, nursing, dentistry, public health, population health), healthcare management (health-focused business administration, nonprofit administration, public institutional administration, etc.), and policy-making (e.g., political science), although not exclusively. This first disease-specific report focuses on the cancer of the uterine cervix (CC). It describes how recent breakthroughs can be leveraged as force multipliers to improve outcomes in CC - by improving early detection, better screening for CC, potential GM-based interventions during the stage of persistent Human papillomavirus (HPV) infection and treatment interventions - especially among the disadvantaged and resource-scarce populations. This work is a tiny step in our attempts to improve outcomes in CC and ultimately eradicate CC from the face of the earth.

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma.

Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO ) sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long-term in situ resistance assay, most osimertinib-resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non-RTK-dependent epithelial-mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib-resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR-mutated LUAD.

Patch formation driven by stochastic effects of interaction between viruses and defective interfering particles.

Defective interfering particles (DIPs) are virus-like particles that occur naturally during virus infections. These particles are defective, lacking essential genetic materials for replication, but they can interact with the wild-type virus and potentially be used as therapeutic agents. However, the effect of DIPs on infection spread is still unclear due to complicated stochastic effects and nonlinear spatial dynamics. In this work, we develop a model with a new hybrid method to study the spatial-temporal dynamics of viruses and DIPs co-infections within hosts. We present two different scenarios of virus production and compare the results from deterministic and stochastic models to demonstrate how the stochastic effect is involved in the spatial dynamics of virus transmission. We compare the spread features of the virus in simulations and experiments, including the formation and the speed of virus spread and the emergence of stochastic patchy patterns of virus distribution. Our simulations simultaneously capture observed spatial spread features in the experimental data, including the spread rate of the virus and its patchiness. The results demonstrate that DIPs can slow down the growth of virus particles and make the spread of the virus more patchy.

SOS2 regulates the threshold of mutant EGFR-dependent oncogenesis.

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance.

An Overview of the Use of Precision Population Medicine in Cancer Care: First of a Series.

Advances in science and technology in the past century and a half have helped improve disease management, prevention, and early diagnosis and better health maintenance. These have led to a longer life expectancy in most developed and middle-income countries. However, resource- and infrastructure-scarce countries and populations have not enjoyed these benefits. Furthermore, in every society, including in developed nations, the lag time from new advances, either in the laboratory or from clinical trials, to using those findings in day-to-day medical practice often takes many years and sometimes close to or longer than a decade. A similar trend is seen in the application of "precision medicine" (PM) in terms of improving population health (PH). One of the reasons for such lack of application of precision medicine in population health is the misunderstanding of equating precision medicine with genomic medicine (GM) as if they are the same. Precision medicine needs to be recognized as encompassing genomic medicine in addition to other new developments such as big data analytics, electronic health records (EHR), telemedicine, and information communication technology. By leveraging these new developments together and applying well-tested epidemiological concepts, it can be posited that population/public health can be improved. In this paper, we take cancer as an example of the benefits of recognizing the potential of precision medicine in applying it to population/public health. Breast cancer and cervical cancer are taken as examples to demonstrate these hypotheses. There exists significant evidence already to show the importance of recognizing "precision population medicine" (PPM) in improving cancer outcomes not only in individual patients but also for its applications in early detection and cancer screening (especially in high-risk populations) and achieving those goals in a more cost-efficient manner that can reach resource- and infrastructure-scarce societies and populations. This is the first report of a series that will focus on individual cancer sites in the future.

Examining the context, logistics, and outcomes of food prescription programs: A scoping review.

BACKGROUND: Obesity and associated metabolic conditions are endemic. Finding new strategies to mitigate the impact on wellbeing and healthcare systems is critical. Food prescription programs (FPPs) have been promoted as one route to address this problem in a way that simultaneously addresses the socio-cultural context of obesity. Yet, little is known about the standard practices and logistics of using food prescription programs as an effective intervention. OBJECTIVES: To 1) identify the context in which food prescription programs are used; 2) identify implementation logistics of food prescription program; and 3) understand the scope of food prescription program outcomes. METHODS: A scoping review was conducted from October 2019 to May 2020 using Google Scholar, EBSCOhost, and AcademicOne Search to identify research articles focused on the implementation of prescription food programs in the US. Updates to articles were made in May of 2021 and May of 2022 to ensure the most up-to-date sample for analysis. There was no publication date restriction for article inclusion. RESULTS: A total of 213 articles were identified for abstract review via the search strategy, and 30 articles were included for analysis following article exclusion. Overall, there was little consistency among included articles regarding the target population, participant recruitment, delivery, and evaluation of the food prescription programs implemented. Most food prescription programs studied were associated with farmers markets, lasted less than 6 months, and utilized produce consumption and biometric data as primary outcomes measures. CONCLUSION: Significant gaps in the literature concerning the long-term effectiveness, impact on health behaviors, screening of eligible participants, and logistics for implementation were identified. Future research should focus on addressing these shortcomings in the current literature to improve the implementation, sustainability, and scaling of food prescription programs.

Changing Role of PET/CT in Cancer Care With a Focus on Radiotherapy.

Positron emission tomography (PET) integrated with computed tomography (CT) has brought revolutionary changes in improving cancer care (CC) for patients. These include improved detection of previously unrecognizable disease, ability to identify oligometastatic status enabling more aggressive treatment strategies when the disease burden is lower, its use in better defining treatment targets in radiotherapy (RT), ability to monitor treatment responses early and thus improve the ability for early interventions of non-responding tumors, and as a prognosticating tool as well as outcome predicting tool. PET/CT has enabled the emergence of new concepts such as radiobiotherapy (RBT), radioimmunotherapy, theranostics, and pharmaco-radiotherapy. This is a rapidly evolving field, and this primer is to help summarize the current status and to give an impetus to developing new ideas, clinical trials, and CC outcome improvements.

A monomethyl auristatin E-conjugated antibody to guanylyl cyclase C is cytotoxic to target-expressing cells in vitro and in vivo.

Guanylyl cyclase C (GCC) is a cell-surface protein that is expressed by normal intestinal epithelial cells, more than 95% of metastatic colorectal cancers (mCRC), and the majority of gastric and pancreatic cancers. Due to strict apical localization, systemically delivered GCC-targeting agents should not reach GCC in normal intestinal tissue, while accessing antigen in tumor. We generated an investigational antibody-drug conjugate (TAK-264, formerly MLN0264) comprising a fully human anti-GCC monoclonal antibody conjugated to monomethyl auristatin E via a protease-cleavable peptide linker. TAK-264 specifically bound, was internalized by, and killed GCC-expressing cells in vitro in an antigen-density-dependent manner. In GCC-expressing xenograft models with similar GCC expression levels/patterns observed in human mCRC samples, TAK-264 induced cell death, leading to tumor regressions and long-term tumor growth inhibition. TAK-264 antitumor activity was generally antigen-density-dependent, although some GCC-expressing tumors were refractory to TAK-264-targeted high local concentrations of payload. These data support further evaluation of TAK-264 in the treatment of GCC-expressing tumors.

Preclinical absorption, distribution, metabolism, excretion and pharmacokinetics of a novel selective inhibitor of breast cancer resistance protein (BCRP).

1. Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma. 2. In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2-/-) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog). 3. ML753286 is a potent inhibitor for BCRP, but not for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) or major cytochrome P450s (CYPs). It has high permeability, but is not an efflux transporter substrate. ML753286 has low to medium clearance in rodent and human liver S9 fractions, and is stable in plasma cross species. Bcrp inhibition affects oral absorption and clearance of sulfasalazine in rodents. A single dose of ML753286 at 50-300 mg/kg orally, and at 20 mg/kg intravenously or 25 mg/kg orally inhibits Bcrp functions in mice and rats, respectively. 4. These findings confirm that ML753286 is a useful selective inhibitor to evaluate BCRP/Bcrp activity in vitro and in rodent model systems.

Synthesis of a new inhibitor of breast cancer resistance protein with significantly improved pharmacokinetic profiles.

The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals.

Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper.

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.

Dose schedule optimization and the pharmacokinetic driver of neutropenia.

Toxicity often limits the utility of oncology drugs, and optimization of dose schedule represents one option for mitigation of this toxicity. Here we explore the schedule-dependency of neutropenia, a common dose-limiting toxicity. To this end, we analyze previously published mathematical models of neutropenia to identify a pharmacokinetic (PK) predictor of the neutrophil nadir, and confirm this PK predictor in an in vivo experimental system. Specifically, we find total AUC and Cmax are poor predictors of the neutrophil nadir, while a PK measure based on the moving average of the drug concentration correlates highly with neutropenia. Further, we confirm this PK parameter for its ability to predict neutropenia in vivo following treatment with different doses and schedules. This work represents an attempt at mechanistically deriving a fundamental understanding of the underlying pharmacokinetic drivers of neutropenia, and provides insights that can be leveraged in a translational setting during schedule selection.

Infrared and Raman spectroscopic studies of tris-[3-(trimethoxysilyl)propyl] isocyanurate, its sol-gel process, and coating on aluminum and copper.

Tris-[3-(trimethoxysilyl)propyl] isocyanurate (TTPI) has been used as a precursor to prepare a sol using ethanol as the solvent under acidic conditions. The sol-gel was applied for the surface treatment of aluminum and copper. Infrared and Raman spectra have been recorded for pure TTPI and the TTPI sol, xerogel and TTPI sol-gel coated metals. From the vibrational spectra, TTPI is likely to have the C1 point group. Vibrational assignments are suggested based on group frequencies, the expected reactions in the sol-gel process and the vibrational studies of some related molecules. From the experimental infrared spectra of xerogels annealed at different temperatures and from the thermal-gravimetric analysis, it is found that the TTPI xerogel decomposes at around 450°C with silica being the major decomposition product. A cyclic voltammetric study of the metal electrodes coated with different concentrations of TTPI ranging from 5% to 42% (v/v) has shown that the films with high concentrations of sol would provide better corrosion protection for aluminum and copper.

Preclinical drug metabolism and pharmacokinetics, and prediction of human pharmacokinetics and efficacious dose of the investigational Aurora A kinase inhibitor alisertib (MLN8237).

Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 µM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.

Preclinical pharmacokinetic/pharmacodynamic/efficacy relationships for alisertib, an investigational small-molecule inhibitor of Aurora A kinase.

PURPOSE: Alisertib (MLN8237) is an investigational inhibitor of Aurora A kinase (AAK). Aurora A plays an essential role in the regulation of spindle assembly and chromosome alignment during mitosis. Inhibition of Aurora A by alisertib in tissue culture has previously been demonstrated to lead to improper chromosomal alignment and disruption of spindle organization, resulting in a transient mitotic delay. The spindle organization defects induced by alisertib have been used to develop a pharmacodynamic (PD) assay for Aurora A inhibition based on the percentage of mitotic cells with proper chromosomal alignment at the metaphase plate (% aligned spindles, abbreviated as AS). The transient mitotic delay that occurs with AAK inhibition permits the use of the mitotic index (the fraction of cells in the population currently undergoing mitosis, abbreviated as MI) as an additional PD assay. When the two PD assays were used in Phase I clinical trials, the reduction in AS was strongly correlated with dose levels and exposures in patients from single time point PD measurements; however, MI failed to show any correlation. To further understand this clinical finding, we constructed PK/PD/efficacy models for AS and MI that can precisely capture the temporal dynamics of the PD markers from in vivo xenograft studies. METHODS: A PK/PD study was conducted using a single oral dose of alisertib at 3, 10, and 20 mg/kg in HCT-116 xenografts implanted subcutaneously in mice. An extravascular, two-compartmental pharmacokinetic (PK) model was used to describe the drug kinetics. Consistent with the mechanistic hypothesis for AAK inhibition, the PD biomarkers such as AS and MI were fitted to PK using a direct response inhibitory sigmoid model and an indirect response turnover model, respectively. The antitumor activity of alisertib dosed orally for 21 days with different dose levels and schedules was evaluated. RESULTS: The PK/PD models showed a fast, sustained response for AS after alisertib administration, whereas MI exhibited a slow, transient response. The PK/efficacy relationship for alisertib in HCT-116 xenografts closely corresponds to the PK/PD relationship for the PD markers, with all three IC50s in close agreement (303, 270, and 280 nM, respectively). CONCLUSION: The PK/PD and PK/efficacy models show that both AS and MI are equally relevant as mechanism-based PD markers to capture drug activity. However, of the two PD markers, the fast, sustained response of AS makes it the only clinically viable PD marker for defining a dose-response relationship, as its maximal effect can be captured from a wider time window with a single PD sampling; while the window to capture dose-related MI response is narrower.

Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism.

Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy and pharmacodynamics of alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we report that alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established, suggesting that Aurora A inhibition may be a promising strategy to increase the efficacy of ara-C. Accordingly, alisertib significantly potentiated the antileukemic activity of ara-C in both AML cell lines and primary blasts. Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the alisertib/ara-C combination, indicating that it is an important regulator of sensitivity to these agents. In vivo studies demonstrated that alisertib significantly augmented the efficacy of ara-C without affecting its pharmacokinetic profile and led to the induction of p27 and BIM. Our collective data indicate that targeting Aurora A with alisertib represents a novel approach to increase the efficacy of ara-C that warrants further investigation.

TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G(2)-M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC(50) values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC(50) >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers.

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor.

Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematological tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approximately a seven-fold increase in the mean plasma area under the concentration-versus-time curve (AUC) compared to the vehicle control group. In mice, after intravenous administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, respectively. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clinically.