Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation.

American Indian cultures: how CBPR illuminated intertribal cultural elements fundamental to an adaptation effort.

The ever-increasing numbers of ethnic minority populations in the USA seeking social services suggest that a "multicultural paradigm shift" is underway and gaining speed. This shift will increasingly demand that prevention programs and interventions be more culturally responsive. Interventions that are not aligned with prospective participants' world views and experiences are only minimally effective. Existing models for conducting culturally grounded program adaptations emphasize identifying distinct levels of cultural influences while preserving core elements of the original intervention. An effective adaptation requires competent language translation as well as trained translations of program concepts and principles that will be meaningful to the targeted group, without compromising program fidelity. This article describes how a university research team and curriculum developers worked with American Indian youth and adults in a large southwestern city using a CBPR process to identify cultural elements that became foundational to the adaptation of a prevention curriculum that is a national model program, with the objective of increasing its applicability for urban native youth.

Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors.

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.

Strategies to resist drug offers among urban American Indian youth of the southwest: an enumeration, classification, and analysis by substance and offeror.

This study explores the drug resistance strategies of urban American Indian adolescents when they encounter people offering them alcohol, cigarettes, and marijuana. Data were collected in 2005 from 11 female and 9 male adolescents who self-identified as American Indian and attended two urban middle schools in the southwestern United States. In two focus groups-one at each school site-the youth described their reactions to 25 hypothetical substance offer scenarios drawn from real-life narratives of similar youth. Qualitative analysis of their 552 responses to the scenarios generated 14 categories. Half of the responses were strategies reported most often by nonnative youth (refuse, explain, leave, and avoid). Using ecodevelopmental theory, the responses were analyzed for indications of culturally specific ways of resisting substance offers, such as variation by specific substance and relationship to the person offering. Study limitations are noted along with suggestive implications for future research on culturally appropriate prevention approaches for urban American Indian youth.

Using Community-based Participatory Research to Adapt keepin' it REAL: Creating a Socially, Developmentally, and Academically Appropriate Prevention Curriculum for 5 Graders.

This paper reports on a process in which program designers, classroom teachers, and students worked together to adapt the 7(th) grade "keepin' it REAL" prevention curriculum to a developmentally, socially, and academically appropriate curriculum for 5(th) graders. A Community-Based Participatory Research methodology (CBPR), combined with a 9-step adaptation model, emphasized a collaborative approach, both transformative and empowering. Essential adaptation elements were the Risk-to-Resiliency Continuum; the teaching of a wide range of skills including risk assessment, decision making, and resistance strategies; and, maintaining the theoretical grounding of Narrative Theory, Communication Competence, and Focus Theory of Norms. This paper describes how CBPR methodology can be conducted successfully while focusing on sustained theoretical grounding and effective research practices in a school-based setting.

Culture in the classroom: developing teacher proficiency in delivering a culturally-grounded prevention curriculum.

The authors describe the training model used to develop proficiency in teaching a culturally-grounded prevention curriculum. Teachers believed it vital to discuss substance use and considered culture and ethnicity central to students' lives, although few had experience teaching prevention curricula. Training effects were evaluated using three datasets. Analyses showed that training should emphasize teaching adult learners; encompass culture from many perspectives; address the teaching of prevention curricula, and emphasize fidelity as imperative. Trainers found the embedded focus on culture in keepin' it REAL essential to success. Teachers learned that a prevention curriculum can be instructionally engaging while theory-driven and academically rigorous.

Immediate and short-term effects of the 5th grade version of the keepin' it REAL substance use prevention intervention.

This study assessed the immediate and short-term outcomes of adapting a culturally-grounded middle school program, keepin' it REAL, for elementary school students. After curriculum adaptation, 10 schools were randomly assigned to the intervention in 5th grade with follow-up boosters in 6th grade; 13 schools were randomly assigned to the control condition, implementing the school's pre-existing substance use prevention programming. Students (n=1566) completed a questionnaire prior to curriculum implementation and follow-up questionnaires toward the end of 5th and 6th grade. The 5th grade kiR curriculum generally appeared no more effective than the control schools' programming in changing students' resistance or decision-making skills; substance use intentions, expectancies, or normative beliefs; or lifetime and recent substance use. Such findings have implications for the age appropriateness of school-based programs.