LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy

Complex Adaptations Can Drive the Evolution of the Capacitor [PSI+], Even with Realistic Rates of Yeast Sex

The [PSI+] prion may enhance evolvability by revealing previously cryptic genetic variation, but it is unclear whether such evolvability properties could be favored by natural selection. Sex inhibits the evolution of other putative evolvability mechanisms, such as mutator alleles. This paper explores whether sex also prevents natural selection from favoring modifier alleles that facilitate [PSI+] formation. Sex may permit the spread of “cheater” alleles that acquire the benefits of [PSI+] through mating without incurring the cost of producing [PSI+] at times when it is not adaptive. Using recent quantitative estimates of the frequency of sex in Saccharomyces paradoxus, we calculate that natural selection for evolvability can drive the evolution of the [PSI+] system, so long as yeast populations occasionally require complex adaptations involving synergistic epistasis between two loci. If adaptations are always simple and require substitution at only a single locus, then the [PSI+] system is not favored by natural selection. Obligate sex might inhibit the evolution of [PSI+]-like systems in other species

Identifying opportunities for engaging the ‘community’ in local alcohol decision-making: a literature review and synthesis

Introduction: Engaging communities in actions to reduce alcohol harms has been identified as an international priority. While there exist recommendations for community engagement within alcohol licensing legislation, there is limited understanding of how to involve communities in local decision-making to reduce harms from the alcohol environment. Methods: A scoping literature review was conducted on community engagement in local government decisionmaking with relevance to the alcohol environment. Academic and grey literature databases were searched between April and June 2018 to identify examples of community engagement in local government in the UK, published since 2000. Texts were excluded if they did not describe in detail the mechanisms or rationale for community engagement. Information was extracted and synthesised through a narrative approach. Results: 3030 texts were identified through the searches, and 30 texts were included in the final review. Only one text described community engagement in alcohol decision-making (licensing); other local government sectors included planning, regeneration and community safety. Four rationales for community engagement emerged: statutory consultation processes; non-statutory engagement; as part of broader participatory initiatives; and community-led activism. While not all texts reported outcomes, a few described direct community influence on decisions. Broader outcomes included improved relationships between community groups and local government. However, lack of influence over decisions was also common, with multiple barriers to effective engagement identified. Conclusion: The lack of published examples of community engagement in local alcohol decision-making relevant to the UK suggests little priority has been placed on sharing learning about supporting engagement in this area. Taking a place-shaping perspective, useful lessons can be drawn from other areas of local government with relevance for the alcohol environment. Barriers to engagement must be considered carefully, particularly around how communities are defined, and how different interests toward the local alcohol environment are represented, or not

On multiplicative structure in Quasi-Newton methods for nonlinear equations

We address the problem how additive and multiplicative structure in the derivatives can be exploited for the construction of Quasi-Newton approximations in smooth nonlinear equations. We derive a model algorithm and show its convergence properties based on a Broyden-like update rule. As a consequence of the use of exact multiplicative parts the convergence factor of the q-linear convergence rate is monotonically decreasing with the norm of the multiplicative part at the solution. Moreover, q-superlinear convergence can be shown, if certain compactness properties are valid, and q-quadratic convergence is obtained, if the multiplicative part vanishes at the solutionAvailable from TIB Hannover: RR 1843(92-22) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target