One example of a kinase inhibitor for which macrocyclization led to improved affinity is Amgen's Pim1/2 inhibitor. These kinases are overexpressed in B-cell malignancies and are targets for the treatment of lymphoma, leukemia, and multiple myeloma. Cyclization in which the connection had the opposite, R, stereochemistry (3) was somewhat less successful, giving potency increases of only ~10-fold in vitro and ~2-fold in cells. X-ray structural analysis of a related macrocycle, 4, bound to Pim1 suggests that no additional interactions were acquired through cyclization of 2, and therefore the increase in potency for this compound compared to 1 is presumably due primarily to the entropic effects of cyclization. More complex or rigid linkers were also tested, none of which gave any further improvement in affinity, having potencies intermediate between those of 1 and 2. However, for reasons of selectivity and pharmacokinetic behavior the variant ultimately selected for clinical development was 4.