Andreas Goutopoulos, Brian Hodous, Ngan Nguyen, Reinaldo Jones, Ben Askew, Lesley Liu-Bujalski, Montserrat Camps, Simone Favre-Zimmerli, Roland Grenningloh, Dusica Santos, Adam Shutes, Mohanraj Dhanabal, Theresa Johnson, Igor Mochalkin, Hui Tian

Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Btk is critical for the activation of these cells and its impairment has been shown to be beneficial in rodent models of lupus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Therefore, Btk inhibitors are expected to be efficacious in various autoimmune diseases, besides their already established utility in B cell malignancies. In autoimmune indications the requirements for better tolerability than in oncology dictate a higher level of kinase selectivity. Using rational drug design, and starting from scaffolds identified by a kinase platform approach, we discovered M2951, an irreversible, covalent, and selective inhibitor of BTK that exhibits an oral pharmacokinetic profile suitable for once daily dosing in man. M2951 is efficacious in different mouse and rat models of human autoimmune disease. In the mouse CIA model of auto-reactive arthritis, the ED₅₀ was 0.75 mg/kg, PO, QD. In a mouse model of SLE in monotherapy, the ED₅₀ was 1.36 mg/kg, PO, QD. Currently, M2951 is in Phase II clinical trials for various autoimmune indications, including Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Multiple Sclerosis.

Christopher M. Yates, Edward P. Garvey, Robert J. Schotzinger, Sam R. Shaver, and William J. Hoekstra

Current fungal CYP51 inhibitors (i.e., "azoles" such as fluconazole and voriconazole) are effective antifungal agents, yet potently inhibit a broad range of off-target human cytochrome P450 enzymes leading to safety liabilities (e.g., drug-drug interactions, liver and reproductive toxicities). We report the discovery of a novel, fungal CYP51-selective agent with broad-spectrum activity. Herein, the triazole heme iron binding group of current agents was replaced with novel, less avid heme iron binding groups in concert with homology-model guided, potency-enhancing scaffold modifications. This process generated VT-1598, an orally available inhibitor that demonstrates high potency against a broad range of yeasts, molds, and endemic fungi. VT-1598 has been granted Qualified Infectious Disease Product (QIDP) and orphan drug designations by the FDA to treat coccidioidomycosis. VT-1598 complements Viamet's yeast- and dermatophyte-active Phase 2B agent VT-1161 under development for both onychomycosis and recurrent vulvovaginal candidiasis.

Mcl-1 is an anti-apoptotic member of the Bcl-2 family of proteins which act via protein–protein interactions between pro- and anti-apoptotic factions to mediate the intrinsic pathway of programmed cell death. Identification of Mcl-1 as a key pro-survival factor in many human cancers and its association with tumor progression and resistance to chemotherapy has made it a highly desirable drug target. Although compelling, targeting disruption of Mcl-1’s protein–protein interaction to induce tumor cell death, was previously thought to be “un-druggable,” due to the high affinities of Mcl-1 to the pro-apoptotic Bcl-2 proteins and lack of a small molecule binding pocket. This presentation will describe the convergence of structural information and small molecule conformational analysis applied to the optimization of a small molecule high-throughput screening hit culminating in the identification of the Mcl-1 inhibitor AMG 176. A phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma patients.

Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer

AMP-activated protein kinase (AMPK) is an evolutionarily conserved pleotropic metabolic regulator that is critical for maintaining cellular energy homeostasis. When cellular energy level is depleted, AMPK gets activated which promotes catabolic processes that result in ATP synthesis while suppressing energy-consuming anabolic processes. The pharmaceutical industry has been seeking enzyme activators of AMPK for the treatment of cardiovascular and metabolic diseases. Through a high-throughput screening employing a novel assay protocol, we identified multiple scaffolds that target distinct AMPK isoforms. The molecular mode of action of these hits was evaluated using a battery of structural, biophysical and kinetic studies. These hits were further optimized to ultimately yield a clinical candidate for diabetic nephropathy. In the presentation, I will describe the Med Chem optimization of the two lead series and biophysical studies of their interactions with AMPK.