Work in Progress: Immigrant Health Care from the Vantage of Cancer Testing and Screening.

This letter offers a perspective from cancer testing and screening on the improvements in immigrant insurance coverage and care charted in Bustamante et al.'s April 2019 article in JOIH on "Health Care Access and Utilization Among U.S. Immigrants Before and After the Affordable Care Act." Supportive evidence for their data may be found in complementary literature drawing from both the National Health Interview Survey the authors use and the Medical Expenditure Panel Survey, while post-ACA surveys and state level information suggest disparities remain for lawfully present and undocumented immigrants ineligible for Medicaid and unable to secure insurance to pay medical costs. Existent options for cancer services are discussed. Further relevant reform depends on voter awareness and collaborative efforts between consumer advocates and legislators.

Shedding light on a HIV blind spot: Factors associated with men's HIV testing in five African countries.

Men's relatively low rates of HIV testing has been termed the 'HIV blind spot' and recently declared by UNAIDS as a top priority. This study uses data from five nationally representative Demographic and Health Surveys in Kenya, Malawi, Mozambique, Zambia, and Zimbabwe to explore factors associated with men's lifetime HIV testing. Between 29.3% and 34.9% of men ages 15-49 in these countries had never tested for HIV and men who held accepting attitudes towards gender-based violence, who lacked HIV knowledge, and who held stigmatising views of HIV were more likely to report never testing for HIV. Findings are interpreted, including a discussion of the possible unintended consequences of current 90-90-90 targets on men's relatively low testing rates. The results point to possible intervention opportunities to increase HIV testing among men in high-HIV prevalence settings in Eastern and Southern Africa and emphasise the importance of changing men's perceptions related to stigma and gender norms.

A sustainable business model for comprehensive medication management in a patient-centered medical home.

OBJECTIVES: To develop a sustainable business model for pharmacist-provided comprehensive medication management services in a patient-centered medical home. Secondarily, to evaluate the impact that the pharmacist had on clinical (glycosylated hemoglobin [A1C], low-density lipoprotein [LDL], and blood pressure) and economic (physician productivity and cost avoidance) outcomes. PRACTICE DESCRIPTION: This pilot project took place at the Palmetto Primary Care Physicians Trident office in North Charleston, South Carolina, from October 2013 to September 2014. At the time, the practice employed 5 physicians and 2 nurse practitioners and served more than 20,000 patients. PRACTICE INNOVATION: The pharmacist targeted patients with diabetes, lipid disorders, hypertension, congestive heart failure, obesity, polypharmacy, and treatment regimen nonadherence for his comprehensive medication management services. The pharmacist was available for immediate consultation or referrals by appointment 5 days per week. Services provided by the pharmacist were billed as medication therapy management or "incident to" physician evaluation and management services codes. EVALUATION: Number of patients seen per day, revenue collected from services rendered by the pharmacist, physician productivity and payment, cost avoidance, and health quality metrics (A1C, LDL, and blood pressure) were measured to determine the financial sustainability and clinical impact of the project. RESULTS AND IMPLICATIONS: The pharmacist was able to see an average of 11 patients per day, which was 72% of his capacity. The practice collected about $7400 per month for services rendered by the pharmacist. The average daily payment for services rendered by the physicians in the practice increased by 20.6%. More than 70% of uncontrolled patients had an improvement in clinical outcomes, such as A1C, LDL, and blood pressure. CONCLUSION: This project demonstrates the sustainable business model for embedding a pharmacist into a patient-centered medical home.

MLN3126, an antagonist of the chemokine receptor CCR9, ameliorates inflammation in a T cell mediated mouse colitis model.

C-C chemokine receptor 9 (CCR9) is the homing receptor for C-C motif chemokine ligand 25 (CCL25), and contributes to the maintenance of mucosal immunity and pathogenesis of inflammatory bowel disease (IBD) through the recruitment of T cells into the gut mucosa. Recent reports suggest that the interaction of CCR9 and CCL25 in the large intestine correlate with disease severity of colonic IBD. MLN3126 is an orally available small molecular compound with potent and selective CCR9 antagonist activity. MLN3126 inhibited CCL25-induced calcium mobilization in human CCR9 transfected cells and CCL25-induced chemotaxis of mouse primary thymocytes in a dose-dependent manner. The potential effect of MLN3126 in an activated T cell transfer mouse colitis model was compared with that of an anti-tumor necrosis factor (TNF)-α antibody. CCL25 protein was detected in the colon of mucosal epithelial cells and CCR9+ CD4+ T cells were observed in the lamina propria of the colon of mice with colitis. Dietary administration of MLN3126 to the mice maintained sufficient concentration of the compound in the plasma and dose-dependently inhibited progression of colitis compared to the vehicle control group. Anti-TNF-α antibody, a surrogate for a standard of care for IBD treatment, was also efficacious in the colitis model. These results suggest that MLN3126 would be a promising orally available CCR9 antagonist to treat colonic IBD.

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.

Adherence to gender-typical behavior and high frequency substance use from adolescence into young adulthood.

Substance use is prevalent among adolescents in the U.S., especially males. Understanding the cross-sectional and longitudinal associations between gender norms and substance use is necessary to tailor substance use prevention messages and efforts appropriately. This study investigates the relationship between adherence to gender-typical behavior (AGB) and substance use from adolescence into young adulthood. Participants in the National Longitudinal Study of Adolescent to Adult Health completed self-report measures on the frequency of binge drinking, cigarette smoking and marijuana use as well as various behaviors and emotional states that captured the latent construct of AGB. Sex-stratified logistic regression models revealed cross-sectional and longitudinal relationships between AGB and high frequency substance use. For example, an adolescent male who is more gender-adherent, compared to less adherent males, has 75% higher odds of high frequency binge drinking in adolescence and 22% higher odds of high frequency binge drinking in young adulthood. Sex-stratified multinomial logistic regression models also revealed cross-sectional and longitudinal relationships between AGB and patterns of use. For example, a more gender-adherent adolescent male, compared to one who is less adherent, is 256% more likely to use all three substances in adolescence and 66% more likely to use all three in young adulthood. Cross-sectional and longitudinal results for females indicate greater gender-adherence is associated with lower odds of high frequency substance use. These findings indicate adherence to gender norms may influence substance use behaviors across the developmental trajectory, and inform strategies for prevention efforts.

A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment.

The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

Toward 90-90-90: identifying those who have never been tested for HIV and differences by sex in Lesotho.

To reach HIV epidemic control it is important to ensure that those who have never been tested access HIV testing and counseling (HTC) particularly in the context of a generalized HIV epidemic. Using data from the 2014 Lesotho Demographic Health Survey bivariate and multivariate logistic regressions were conducted to determine the associations between never tested for HIV and key socio-cognitive characteristics by sex. Marginal probabilities at the means were calculated for the socio-cognitive variables for men and women to ascertain the magnitude of the differences in the likelihood of never being tested by sex. We stratified by gender and controlled for age, education, religion, marital status, place of residence, and years circumcised (for men only). Results indicate that more men than women have never been tested (χ2 = 461.16, p < 0.001); and, among men, acceptance of gender based violence (Odds ratio [OR]: 1.44, p < 0.001), holding discriminatory attitudes (OR: 1.50, p < 0.001), and not having basic HIV prevention knowledge (OR: 1.53, p < 0.001) were significantly associated with never being tested. The likelihood of never being tested among those who had these three socio-cognitive characteristics was much higher among men (0.56, p < 0.001) than women (0.20, p < 0.001). Given the strong sex differential, there is an urgent need for strategies specifically targeting men in order to effectively promote HTC uptake among them. Additionally, results suggest that those strategies should integrate strategies to address GBV acceptance, HIV prevention knowledge, and HIV discrimination or link men to programs addressing these.

Probiotics for the prevention of surgical necrotising enterocolitis: systematic review and meta-analysis.

AIM OF THE STUDY: Probiotic administration to preterm infants has the potential to prevent necrotising enterocolitis (NEC). Data from randomised controlled trials (RCT) are conflicting but meta-analyses seem to support this intervention. To date, these analyses have not focused on surgical NEC. We aimed to determine the effect of probiotic administration to preterm infants on prevention of surgical NEC. METHODS: A systematic review of RCTs of probiotic administration to preterm infants was performed. Studies were included if RCT outcomes included any of (1) Bell's stage 3 NEC; (2) surgery for NEC; and (3) deaths attributable to NEC. Article selection and data extraction were performed independently by two authors; conflicts were adjudicated by a third author. Data were meta-analysed using Review Manager V.5.3. A random effects model was decided on a priori because of the heterogeneity of study design; data are risk ratio (RR) with 95% CI. MAIN RESULTS: Thirty-five RCTs reported NEC as an outcome. Seventeen reported surgical NEC; all RCTs were included. A variety of probiotic products was administered across studies. Description of surgical NEC in most studies was poor. Only 6/16 specifically reported incidence of surgery for NEC, 12/17 Bell's stage 3 and 13/17 NEC-associated mortality. Although there was a trend towards probiotic administration reducing stage 3 NEC, this was not significant (RR 0.74 (0.52-1.05), p=0.09). There was no effect of probiotics on the RR of surgery for NEC (RR 0.84 (0.56-1.25), p=0.38). Probiotics did, however, reduce the risk of NEC-associated mortality (RR 0.56 (0.34-0.93), p=0.03). CONCLUSION: Despite 35 RCTs on probiotic prevention of NEC, evidence for prevention of surgical NEC is not strong, partly due to poor reporting. In studies included in this meta-analysis, probiotic administration was associated with a reduction in NEC-related mortality.

What role can gender-transformative programming for men play in increasing men's HIV testing and engagement in HIV care and treatment in South Africa?

Men are less likely than women to test for HIV and engage in HIV care and treatment. We conducted in-depth interviews with men participating in One Man Can (OMC) - a rights-based gender equality and health programme intervention conducted in rural Limpopo and Eastern Cape, South Africa - to explore masculinity-related barriers to HIV testing/care/treatment and how participation in OMC impacted on these. Men who participated in OMC reported an increased capability to overcome masculinity-related barriers to testing/care/treatment. They also reported increased ability to express vulnerability and discuss HIV openly with others, which led to greater willingness to be tested for HIV and receive HIV care and treatment for those who were living with HIV. Interventions that challenge masculine norms and promote gender equality (i.e. gender-transformative interventions) represent a promising new approach to address men's barriers to testing, care and treatment.

Novel diversity-oriented synthesis-derived respiratory syncytial virus inhibitors identified via a high throughput replicon-based screen.

Respiratory syncytial virus (RSV) infections affect millions of children and adults every year. Despite the significant disease burden, there are currently no safe and effective vaccines or therapeutics. We employed a replicon-based high throughput screen combined with live-virus triaging assays to identify three novel diversity-oriented synthesis-derived scaffolds with activity against RSV. One of these small molecules is shown to target the RSV polymerase (L protein) to inhibit viral replication and transcription; the mechanisms of action of the other small molecules are currently unknown. The compounds described herein may provide attractive inhibitors for lead optimization campaigns.

Transiciones a la adultez: exploración sobre las relaciones románticas y normativas de masculinidad de los adolescentes en el Bañado Sur, Asunción / Transitions to adulthood: exploration of romantic relationships and norms of masculinity adolescents in Bañado Sur, Asunción

Introducción: muchas veces los hombres jóvenes se definen a sí mismos y a su identidad masculina a través de relaciones románticas y sexuales; sus decisiones sexuales pueden afectar su transición hacia la madurez, así como la adquisición de infecciones de transmisión sexual, VIH y tasas de embarazos. Objetivo: Este artículo analiza cómo influyen en el modo en que actúan en las relaciones sexuales y románticas y la formación de su identidad masculina, los grupos de amigos de hombres jóvenes paraguayos, sus familias. Metodología: En el 2010 llevamos a cabo cinco charlasen grupo en Asunción, Paraguay, en las que se examinaron las normas comunitarias con grupos de adolescentes entre 14 y 19 años de edad. Luego entrevistamos a la mitad de los miembros de cada grupo para examinar sus relaciones con amigos, la familia, mujeres jóvenes y sus creencias sobre las normas de género existentes. Resultados: Los jóvenes describieron dos tipos de normas masculinas (“pareja/proveedor” y “macho”) y dos tipos de relaciones románticas (“casual” y “formal”). Muchas veces se encontró una concordancia en el lenguaje utilizado para describir cada abanico de conductas, lo que pone de relieve la relación existente entre las normas masculinas y las relaciones románticas.

Introduction: Many times young men define themselves and their male identity through romantic and sexual relationships; their sexual decisions can affect their transition to adulthood as well as the acquisition of sexually transmitted infections, HIV and pregnancy rates. Objective:This article discusses how to influence the waythey act in sexual and romantic relationshipsand the formation of their male identity, groupsof young men Paraguay an friends, their families. Methodology: In 2010 we conducted five talks group in Asuncion, Paraguay, in which Community rules were examined with groups of teenagers between 14 and 19 years old. Then we interviewed half of the members of each group to examine their relationships with friends, family, young women and their beliefs about existing gender norms. Results: Young described two types of male norms(“partner / supplier” and “male”) and two types of romantic relationships (“casual” and “formal”).Many times a match was found in the languageused to describe each range of behaviors, which highlights the relationship between male normsand romantic relationships. The rules received bythe neighborhood as models that were more machobehavior by young people themselves informedcharacteristics. The rules can not be changed unlessyoung people talk about their behavior clearly notnormative. This demonstrates that further studieson the formation, meaning and transformation of male standards are needed.

Proteasome inhibitors bortezomib and carfilzomib used for the treatment of multiple myeloma do not inhibit the serine protease HtrA2/Omi.

The proteasome inhibitor bortezomib is associated with the development of peripheral neuropathy in patients, but the mechanism by which bortezomib can induce peripheral neuropathy is not fully understood. One study suggested that off-target inhibition of proteases other than the proteasome, particularly HtraA2/Omi, may be the underlying mechanism of the neuropathy. The same study also concluded that carfilzomib, a second proteasome inhibitor that is associated with less peripheral neuropathy in patients than bortezomib, showed no inhibition of HtrA2/Omi. The goal of the work described here was to determine whether either proteasome inhibitors truly affected HtrA2/Omi activity. A variety of methods were used to test the effects of both bortezomib and carfilzomib on HtrA2/Omi activity that included in vitro recombinant enzyme assays, and studies with the human neuroblastoma SH-SY5Y cell line and HtrA2/Omi-knockout mouse embryonic fibroblasts. The compound ucf-101 was used to assess the effects of specific HtrA2/Omi inhibition. In contrast to previously published data, our results clearly demonstrated that neither bortezomib nor carfilzomib inhibited HtrA2/Omi activity in recombinant enzyme assays at concentrations up to 100 µM, while the specific inhibitor ucf-101 did inhibit the enzyme. The proteasome inhibitors did not inhibit HtrA2/Omi activity in either SH-SY5Y cells or mouse embryonic fibroblasts, as determined by expression of the HtrA2/Omi substrates eIF4G1 and UCH-L1. Based on our biochemical and cell-based assays, we conclude that neither bortezomib nor carfilzomib inhibited HtrA2/Omi activity. Therefore, it is unlikely that bortezomib associated peripheral neuropathy is a direct result of off-target inhibition of HtrA2/Omi.

Probiotics and necrotizing enterocolitis.

Probiotics for the prevention of necrotizing enterocolitis have attracted a huge interest. Combined data from heterogeneous randomised controlled trials suggest that probiotics may decrease the incidence of NEC. However, the individual studies use a variety of probiotic products, and the group at greatest risk of NEC, i.e., those with a birth weight of less than 1000 g, is relatively under-represented in these trials so we do not have adequate evidence of either efficacy or safety to recommend universal prophylactic administration of probiotics to premature infants. These problems have polarized neonatologists, with some taking the view that it is unethical not to universally administer probiotics to premature infants, whereas others regard the meta-analyses as flawed and that there is insufficient evidence to recommend routine probiotic administration. Another problem is that the mechanism by which probiotics might act is not clear, although some experimental evidence is starting to accumulate. This may allow development of surrogate endpoints of effectiveness, refinement of probiotic regimes, or even development of pharmacological agents that may act through the same mechanism. Hence, although routine probiotic administration is controversial, studies of probiotic effects may ultimately lead us to effective means to prevent this devastating disease.

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.

We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56 µM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.

Recruitment of bone marrow-derived valve interstitial cells is a normal homeostatic process.

Advances in understanding of the maintenance of the cardiac valves during normal cardiac function and response to injury have led to several novel findings, including that there is contribution of extra-cardiac cells to the major cellular population of the valve: the valve interstitial cell (VIC). While suggested to occur in human heart studies, we have been able to experimentally demonstrate, using a mouse model, that cells of bone marrow hematopoietic stem cell origin engraft into the valves and synthesize collagen type I. Based on these initial findings, we sought to further characterize this cell population in terms of its similarity to VICs and begin to elucidate its contribution to valve homeostasis. To accomplish this, chimeric mice whose bone marrow was repopulated with enhanced green fluorescent protein (EGFP) expressing total nucleated bone marrow cells were used to establish a profile of EGFP(+) valve cells in terms of their expression of hematopoietic antigens, progenitor markers, fibroblast- and myofibroblast-related molecules, as well as their distribution within the valves. Using this profile, we show that normal (non-irradiated, non-transplanted) mice have BM-derived cell populations that exhibit identical morphology and phenotype to those observed in transplanted mice. Collectively, our findings establish that the engraftment of bone marrow-derived cells occurs as part of normal valve homeostasis. Further, our efforts demonstrate that the use of myeloablative irradiation, which is commonly employed in studies involving bone marrow transplantation, does not elicit changes in the bone marrow-derived VIC phenotype in recipient mice.

Preclinical evaluation of the antitumor activity of bortezomib in combination with vitamin C or with epigallocatechin gallate, a component of green tea.

PURPOSE: To investigate whether clinically relevant levels of epigallocatechin gallate (EGCG, a component of green tea) or vitamin C (ascorbic acid) could antagonize bortezomib antitumor activity in CWR22 human prostate xenograft tumors. METHODS: The pharmacokinetics (PK) of EGCG and ascorbic acid were determined in immunocompromised mice and compared with concentrations measured in human PK studies of dietary supplements. Antitumor activity of bortezomib in combination with EGCG or ascorbic acid was determined using several dosing regimens to evaluate different target plasma concentrations of EGCG and ascorbic acid. RESULTS: Bortezomib dosed twice-weekly at 0.8 mg/kg IV demonstrated tumor growth inhibition (TGI) of 53.9-58.9%. However, when combined with EGCG such that the plasma concentrations of EGCG were >200 µM at the time of bortezomib dosing, all antitumor activity was abrogated (TGI = -17.7%). A lower concentration of EGCG (11-16 µM), which is severalfold higher than measured clinically in humans taking EGCG supplements (0.6-3 µM), was not antagonistic to bortezomib (TGI 63.5%). Pharmacodynamic studies of proteasome inhibition reflected these findings. Ascorbic acid (40 and 500 mg/kg PO daily) was evaluated under a similar study design and did not antagonize bortezomib antitumor activity (TGI 57.2 and 72.2%). CONCLUSIONS: No antagonism of bortezomib is seen in preclinical in vivo experiments, where EGCG or ascorbic acid plasma concentrations are commensurate with dietary or supplemental intake. The data suggest that patients receiving bortezomib treatment do not need to avoid normal dietary consumption of green tea, vitamin C-containing foods, or EGCG or vitamin C dietary supplements.

An exploration of public knowledge of warning signs for cancer.

BACKGROUND: Warning signs of cancer have long been used as an effective way to summarise and communicate early indications of cancer to the public. Given the increasing global burden of cancer, the communication of these warning signs to the public is more important than ever before. AIM: This paper presents part of a larger study which explored the attitudes, knowledge and behaviours of people in mid-life towards cancer prevention. The focus of this paper is on the assessment of the knowledge of members of the public aged between 35 and 54 years of age. METHOD: A questionnaire was administered to a representative sample of the population listing 17 warning signs of cancer. These included the correct warning signs and distracter signs. Respondents were asked to correctly identify the seven warning signs. RESULTS: Findings show that respondents could identify 4.8 cancer warning signs correctly. Analysis by demographics shows that being female, being older, having a higher level of educational attainment and being in a higher socio-economic group are predictors of better level of knowledge of cancer warning signs. RECOMMENDATIONS: Recommendations are proffered with regard to better targeting, clarification and communication of cancer warning signs.

Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.

The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.

Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer.

The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.