3 research outputs found
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
Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta
Human DNA polymerase theta (Polθ), which is essential
for
microhomology-mediated DNA double strand break repair, has been proposed
as an attractive target for the treatment of BRCA deficient and other
DNA repair pathway defective cancers. As previously reported, we recently
identified the first selective small molecule Polθ in vitro
probe, 22 (ART558), which recapitulates the phenotype
of Polθ loss, and in vivo probe, 43 (ART812), which
is efficacious in a model of PARP inhibitor resistant TNBC in vivo.
Here we describe the discovery, biochemical and biophysical characterization
of these probes including small molecule ligand co-crystal structures
with Polθ. The crystallographic data provides a basis for understanding
the unique mechanism of inhibition of these compounds which is dependent
on stabilization of a “closed” enzyme conformation.
Additionally, the structural biology platform provided a basis for
rational optimization based primarily on reduced ligand conformational
flexibility
Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta
Human DNA polymerase theta (Polθ), which is essential
for
microhomology-mediated DNA double strand break repair, has been proposed
as an attractive target for the treatment of BRCA deficient and other
DNA repair pathway defective cancers. As previously reported, we recently
identified the first selective small molecule Polθ in vitro
probe, 22 (ART558), which recapitulates the phenotype
of Polθ loss, and in vivo probe, 43 (ART812), which
is efficacious in a model of PARP inhibitor resistant TNBC in vivo.
Here we describe the discovery, biochemical and biophysical characterization
of these probes including small molecule ligand co-crystal structures
with Polθ. The crystallographic data provides a basis for understanding
the unique mechanism of inhibition of these compounds which is dependent
on stabilization of a “closed” enzyme conformation.
Additionally, the structural biology platform provided a basis for
rational optimization based primarily on reduced ligand conformational
flexibility