Predictive design of guest-responsive frameworks on the molecular level is still a major challenge for experimental and theoretical chemists. The isoreticular approach is one of the most promising approaches for designing MOFs with desired textural properties and framework topology. In this work we successfully applied the isoreticular approach for the design of the new flexible frameworks DUT-180 and DUT-190, constructed by square planar or octahedral metal nodes and a tetracarboxylate ligand. The flexibility mechanism in DUT-190 was explored using in situ PXRD and NMR in parallel to physisorption of subcritical gases such as nitrogen (77 K), carbon dioxide (195 K) and xenon (206 K). Methane physisorption experiments, conducted in a broad temperature range indicate a softening of the DUT-190 framework compared to its analogue DUT-13. These experimental and computational findings can be used as a roadmap for discovery of new flexible frameworks with desired micromechanical properties.