Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

Apoptosis signal-regulating kinase 1 (ASK1/ MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury. KEYWORDS:Apoptosis signal-regulating kinase 1 (ASK1), structure-based drug design (SBDD), cardiac injury A poptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) family member residing upstream of both Jun N-terminal kinase (JNK) and p38. ASK1 is capable of activating JNK and P38 via the phosphorylation of intermediate kinases. ASK1 plays a role in the mammalian cell stress response and the induction of apoptotic cell death. It also contributes to a range of systemic diseases including heart failure 1 and acute ischemia/reperfusion injury, by reducing structural and functional integrity of the mitochondria in cardiac cells. 2−4 ASK1-deficient mice display reduced levels of cardiomyocyte apoptosis, hypertrophy, and interstitial fibrosis. 5 Thus, selective inhibition of ASK1 represents an attractive strategy for slowing or potentially reversing harmful tissue changes associated with various forms of heart failure.Using ASK1 structural information and deconstruction of known ASK1 inhibitors such as 1 and 2 (Figure 1), our research team generated a novel, potent, and orally bioavailable ASK1 inhibitor with favorable physicochemical properties to help further elucidate the role of ASK1 in cardiac injury. Compound 1 was an early lead for Takeda's ASK1 inhibitor program. 6 Compound 2 (GS-4997, Gilead Sciences) is a clinical stage ASK1 inhibitor, which has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis. 7 Key structural features with respect to ligand interactions within the ATP binding site were identified using our internal database as well as public domain crystal structures of small molecules in ASK1 and published pharmacophore models. 8,9 Figure 1 illustrates the cocrystal structure of 1 in hASK1 (PDB: 3VW6) and highlights the key interactions between 1 and the ASK1 ATP binding pocket. Binding to the kinase hinge is characterized by a hydrogen bonding interaction with the

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The new bis(sulfonamide) bis(pyridyl) ligand 1 readily binds to copper(II) in a tetradentate fashion giving monomeric, dimeric, and polymeric complexes. The solid state structures of these compounds were found to depend on the use of racemic vs resolved ligand.