Cell-Active, Irreversible Covalent Inhibitors Targeting a Surface-Exposed Non-Catalytic Lysine on Aurora a Kinase by Using Squarate Chemistry.

Targeting surface-exposed lysines in kinases through covalent modification presents a major challenge due to their high pK and inherently low reactivity. While current research primarily targets more reactive catalytic lysines buried in the ATP-binding pocket, no systematic rational strategy has yet been developed for selectively engaging surface-exposed lysines. Herein, we present a versatile strategy for developing cell-active covalent kinase inhibitors (CKIs) by selectively targeting unique surface-exposed lysines using squarate chemistry.

Cell-Active, Arginine-Targeting Irreversible Covalent Inhibitors for Non-Kinases and Kinases.

Targeted covalent inhibitors (TCIs) play an essential role in the fields of kinase research and drug discovery. TCI strategies to target more common amino acid side-chains have yet to be demonstrated. Targeting other amino acids would also expand the pharmaceutical industry's toolbox for targeting other tough-to-drug proteins.

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations.

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.

TRK xDFG mutation-induced acquired resistance of 1 generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKA with IC values of 3.

Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance.

Tropomyosin receptor kinase (TRK) secondary mutations mediating acquired resistance, especially at the solvent-front (SF) and the DFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinase inhibitors have displayed significant advantages in overcoming clinical resistance driven by kinase mutations; however, all reported small-molecule macrocyclic TRK inhibitors are all type I inhibitors and are therefore much more sensitive to SF than xDFG mutations. Novel therapeutics for patients with xDFG resistance mutations are urgently needed.

Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies.

Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits.