Aleksey I. Gerasyuto

Discovery of 2H-Pyrrolo[3,4- c ]pyridin-3-one Derivatives as Type-III c-MET Inhibitors Enabled by Free-Energy Perturbation Calculations

Éric Therrien, Shulu Feng, Katherine Amberg-Johnson, Nadim Shaikh et autres

The clinical emergence of diverse c-MET mutations with resistance to approved inhibitors has created an urgent demand for next-generation inhibitors with efficacy against c-MET-resistant mutations while maintaining c-MET wild-type (WT) potency, selectivity over other kinases, and brain penetration. Here, we report a …

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Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study

Jennifer L. Knight, Anthony J. Clark, Jiashi Wang, Andrew Placzek et autres

Optimizing both on-target and off-target potencies is essential for developing effective and selective small-molecule therapeutics. Free energy calculations offer rapid potency predictions, usually within hours and with experimental accuracy and thus enables efficient identification of promising compounds for synthesis, accelerating early-stage drug …

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Abstract 3025: Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models

Shaoxian Sun, Felicia Gray, Sarah Silvergleid, Robert Pelletier et autres

Abstract Background: Cancer cells often have deregulated G1-S phase in cell cycle and rely on the G2-M checkpoint to delay mitosis allowing for completed DNA damage repair. Wee1 and Myt1 kinases regulate G2 to M phase transition by inhibitory phosphorylation of cyclin …

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Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform

Hideyuki Igawa, Zef A. Könst, Éric Therrien, Mee Shelley et autres

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and …

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The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis

Bryce A. Harrison, James J. Dowling, Matthew G. Bursavich, Dawn M. Troast et autres

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the …

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AutoDesigner - Core Design, a De Novo Design Algorithm for Chemical Scaffolds: Application to the Design and Synthesis of Novel Selective Wee1 Inhibitors

Pieter H. Bos, Fabio Ranalli, E. A. Flood, Shawn Watts et autres

The hit identification stage of a drug discovery program generally involves the design of novel chemical scaffolds with desired biological activity against the target(s) of interest. One common approach is scaffold hopping, which is the manual design of novel scaffolds based on …

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147 (PB135): Discovery of SGR-3515, a first-in-class Wee1/Myt1 inhibitor with differentiated pharmacological properties in xenograft tumor models

Shaoxian Sun, Sarah Silvergleid, Felicia Gray, Robert Pelletier et autres

Harnessing free energy calculations to achieve kinome-wide selectivity in drug discovery campaigns: Wee1 case study

Jennifer L. Knight, Anthony J. Clark, Jiashi Wang, Andrew Placzeck et autres

Free energy calculations are revolutionizing early-stage drug-discovery campaigns. Robust free energy methods can rapidly provide accurate on-target and off-target potency predictions to identify promising chemical matter for synthesis, thus, inspiring further rounds of ideation and optimization. Here, we present a free energy …

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Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using in silico Enabled Drug Discovery Platform

Hideyuki Igawa, Zef A. Könst, Éric Therrien, Mee Shelley et autres

Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment of non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to the …

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Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using in silico Enabled Drug Discovery Platform

Hideyuki Igawa, Zef Konst, Éric Therrien, Mee Shelley et autres

Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment of non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to the …

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AutoDesigner - Core Design, a De Novo Design Algorithm for Chemical Scaffolds: Application to the Design and Synthesis of Novel Selective Wee1 Inhibitors

Pieter H. Bos, Fabio Ranalli, E. A. Flood, Shawn Watts et autres

The hit identification stage of a drug discovery program generally involves the design of novel chemical scaffolds with desired biological activity against the target(s) of interest. One common approach is scaffold hopping, which is the manual design of novel scaffolds based on …

us (code pays fourni par la source)

AutoDesigner - Core Design, a De Novo Design Algorithm for Chemical Scaffolds: Application to the Design and Synthesis of Novel Selective Wee1 Inhibitors

Pieter H. Bos, Fabio Ranalli, E. A. Flood, Shawn Watts et autres

The hit identification stage of a drug discovery program generally involves the design of novel chemical scaffolds with desired biological activity against the target(s) of interest. One common approach is scaffold hopping, which is the manual design of novel scaffolds based on …

us (code pays fourni par la source)