A5089086635- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Colorectal Cancer Treatments and Studies
- Cancer therapeutics and mechanisms
- DNA Repair Mechanisms
- Melanoma and MAPK Pathways
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Asymmetric Synthesis and Catalysis
- Alkaloids: synthesis and pharmacology
- ATP Synthase and ATPases Research
- Asymmetric Hydrogenation and Catalysis
- Computational Drug Discovery Methods
- Cell death mechanisms and regulation
- Tryptophan and brain disorders
- Microtubule and mitosis dynamics
- Fluorine in Organic Chemistry
- Cancer Research and Treatments
- Chemical Synthesis and Analysis
- Traditional and Medicinal Uses of Annonaceae
- Peptidase Inhibition and Analysis
- Medical Imaging Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
La Roche College
2015
Genentech
2010-2012
The University of Texas at Austin
1999-2002
Imperial College London
1996
The London College
1996
A series of compounds were designed and synthesized as antagonists cIAP1/2, ML-IAP, XIAP based on the N-terminus, AVPI, mature Smac. Compound 1 (GDC-0152) has best profile these compounds; it binds to BIR3 domain, BIR domain domains cIAP1 cIAP2 with K(i) values 28, 14, 17, 43 nM, respectively. These promote degradation cIAP1, induce activation caspase-3/7, lead decreased viability breast cancer cells without affecting normal mammary epithelial cells. inhibits tumor growth when dosed orally...
Antibody–drug conjugate therapy entails targeted killing of cancer cells with cytotoxic compounds covalently linked to tumor-specific antibodies and shows promise in the treatment several human cancers. Current antibody–drug designs that incorporate a disulfide linker between antibody drug are inspired by indirect evidence suggesting redox potential within endosomal system is reducing. It presumed antigen-dependent endocytosis leads reduction intracellular release free drug, but direct...
Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that limitations of FRAX1036 (1) were chiefly associated highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified an effective means reducing pKa logP simultaneously. When positioned properly within scaffold, this group conferred benefits...
p21-activated kinase 1 (PAK1) has an important role in transducing signals several oncogenic pathways. The concept of inhibiting this garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity a narrow therapeutic window. To attempt mitigating toxicity, we introduced structural changes,...
Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss activity resulted in an increase function and tumor growth inhibition glioma models. Herein, we describe discovery series small molecule inhibitors HPK1. Using structure-based drug design approach, selectivity molecules was significantly improved by inducing stabilizing unusual P-loop folded binding...
Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number cancers; therefore, TDO inhibition may be useful therapeutic intervention for cancers. We identified an aminoisoxazole series as potent inhibitors from high-throughput screen (HTS). An extensive medicinal chemistry effort revealed that both amino group and isoxazole moiety are important inhibitory activity. Computational...
Checkpoint kinase 1 (ChK1) is a serine/threonine that functions as central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation downstream effectors delays progression so damaged genome can be repaired. As therapeutic strategy, inhibition ChK1 should potentiate antitumor effect chemotherapeutic agents by inactivating postreplication checkpoint, causing premature entry into mitosis with resulting in mitotic...
A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation TDO as potential cancer immunotherapy target. As means mitigating the risk drug–drug interactions arising from cytochrome P450 inhibition, novel property-based parameter, herein referred to CYP Index,...
Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation immune function and has demonstrated synergy checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use selective small molecule immunotherapy. We identified novel series isoquinoline through fragment-based screening that displayed promising levels biochemical...
Transition metal mediated isomerisation of allylic alkoxides is presented as a new method for enolate anion generation. The scope and limitations formation with the catalysts [Rh(dppe)(THF)2]+ClO4– (Ph3P)3RhCl are explored synthetic potential methodology demonstrated in stereoselective reactions certain ketone aldehyde enolates.
Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads hypothesis that inhibition of ChK1 might enhance effectiveness DNA-damaging therapies treatment cancer. Lead compound (GNE-783), prototype 1,7-diazacarbazole class inhibitors, was found be highly potent inhibitor acetylcholine esterase (AChE) and unsuitable development. A campaign analogue synthesis established SAR delineating AChE...
A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (1) was developed. Highlights include protection pyrrole ring a 1,7-diazacarbazole as propyl ethyl ether, an efficient Pd catalyzed cyanation aryl chloride, ether formation by SNAr fluoride displacement, and development controlled crystallization providing API with required polymorphic form. The delivered high-quality low levels impurities residual metals in five steps 31% overall yield.
Oncogenic KRAS mutations were identified decades ago, yet the selective inhibition of specific mutant proteins represents an ongoing challenge. Recent progress has been made in targeting certain P-loop proteins, particular G12C, for which covalent GDP state via Switch II pocket is now a clinically validated strategy. Inhibition other such as G13D, on hand, still requires clinical validation. The remoteness D13 residue relative to combination with solvent exposure and conformational...