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

Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe <b>NI-57</b> (<b>16</b>) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor <b>16</b> preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound <b>16</b> has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with <b>16</b> was demonstrated in nanoBRET and FRAP assays. The binding of <b>16</b> to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show <b>16</b> has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for <b>16</b> was generated in mouse with single dose administration showing favorable oral bioavailabilit

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit <b>5b</b> to <b>13-d</b> as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of <b>13-d</b> in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that <b>13-d</b> had properties compatible with oral dosing in mouse models of disease (<i>F</i>_po 49%). We propose that <b>NI-42</b> (<b>13-d</b>) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins