Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Continuous collective analysis of chemical reactions.

The automated synthesis of small organic molecules from modular building blocks has the potential to transform our capacity to create medicines and materials. Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed.

Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). With the aim of understanding and modulating neosubstrate specificity, we recently reported the discovery of SJ3149 (), a selective and potent molecular glue degrader of CK1α, that is active in multiple cancer cell lines. Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders.

Development of an Orally Bioavailable LCK PROTAC Degrader as a Potential Therapeutic Approach to T-Cell Acute Lymphoblastic Leukemia.

Despite significant advances over recent years, the treatment of T cell acute lymphoblastic leukemia (T-ALL) remains challenging. We have recently shown that a subset of T-ALL cases exhibited constitutive activation of the lymphocyte-specific protein tyrosine kinase (LCK) and were consequently responsive to treatments with LCK inhibitors and degraders such as dasatinib and dasatinib-based PROTACs. Here we report the design, synthesis and evaluation of SJ45566, a potent and orally bioavailable LCK PROTAC.

Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.

Sonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness.