Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Marian C. Bryan is active.

Publication


Featured researches published by Marian C. Bryan.


Journal of Medicinal Chemistry | 2013

Sustainable Practices in Medicinal Chemistry: Current State and Future Directions

Marian C. Bryan; Barry R. Dillon; Lawrence G. Hamann; Gregory J. Hughes; Michael E. Kopach; Emily A. Peterson; Mehrnaz Pourashraf; Izzat Raheem; Paul Richardson; Daniel Richter; Helen F. Sneddon

The medicinal chemistry subgroup of the American Chemical Societys Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.


Journal of Medicinal Chemistry | 2014

Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.

Emily J. Hanan; Charles Eigenbrot; Marian C. Bryan; Daniel J. Burdick; Bryan K. Chan; Yuan Chen; Jennafer Dotson; Robert Heald; Philip Stephen Jackson; Hank La; Michael Lainchbury; Shiva Malek; Hans E. Purkey; Gabriele Schaefer; Stephen Schmidt; Eileen Mary Seward; Steve Sideris; Christine Tam; Shumei Wang; Siew Kuen Yeap; Ivana Yen; JianPing Yin; Christine Yu; Inna Zilberleyb; Timothy P. Heffron

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.


Journal of Medicinal Chemistry | 2012

Rapid Development of Piperidine Carboxamides as Potent and Selective Anaplastic Lymphoma Kinase Inhibitors

Marian C. Bryan; Douglas A. Whittington; Elizabeth M. Doherty; James Richard Falsey; Alan C. Cheng; Renee Emkey; Rachael L. Brake; Richard T. Lewis

Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.


Journal of Medicinal Chemistry | 2011

Discovery of potent, orally bioavailable phthalazinone bradykinin B1 receptor antagonists.

Kaustav Biswas; Tanya Peterkin; Marian C. Bryan; Leyla Arik; Sonya G. Lehto; Hong Sun; Feng-Yin Hsieh; Cen Xu; Robert T. Fremeau; Jennifer R. Allen

The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.


Journal of Medicinal Chemistry | 2015

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.

Robert Heald; Krista K. Bowman; Marian C. Bryan; Daniel J. Burdick; Bryan K. Chan; Emily Chan; Yuan Chen; Saundra Clausen; Belen Dominguez-Fernandez; Charles Eigenbrot; Richard L. Elliott; Emily J. Hanan; Philip Stephen Jackson; Hank La; Michael Lainchbury; Shiva Malek; Sam Mann; Mark Merchant; Kyle Mortara; Hans E. Purkey; Gabriele Schaefer; Stephen Schmidt; Eileen Mary Seward; Steve Sideris; Lily Shao; Shumei Wang; Kuen Yeap; Ivana Yen; Christine Yu; Timothy P. Heffron

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.


ACS Combinatorial Science | 2013

Disubstituted 1-Aryl-4-Aminopiperidine Library Synthesis Using Computational Drug Design and High-Throughput Batch and Flow Technologies

Marian C. Bryan; Christopher D. Hein; Hua Gao; Xiaoyang Xia; Heather Eastwood; Bernd A. Bruenner; Steven W. Louie; Elizabeth M. Doherty

A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times.


ACS Medicinal Chemistry Letters | 2016

Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR.

Marian C. Bryan; Daniel J. Burdick; Bryan K. Chan; Yuan Chen; Saundra Clausen; Jennafer Dotson; Charles Eigenbrot; Richard L. Elliott; Emily J. Hanan; Robert Heald; Philip Stephen Jackson; Hank La; Michael Lainchbury; Shiva Malek; Sam Mann; Hans E. Purkey; Gabriele Schaefer; Stephen Schmidt; Eileen Mary Seward; Steve Sideris; Shumei Wang; Ivana Yen; Christine Yu; Timothy P. Heffron

The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.


Bioorganic & Medicinal Chemistry Letters | 2016

4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.

Emily Hanan; Matt Baumgardner; Marian C. Bryan; Yuan Chen; Charles Eigenbrot; Peter Fan; Xiao-Hui Gu; Hank La; Shiva Malek; Hans E. Purkey; Gabriele Schaefer; Stephen Schmidt; Steve Sideris; Ivana Yen; Christine Yu; Timothy P. Heffron

The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell lung cancers with the T790M resistance mutation remains a significant unmet medical need. We report the identification of 4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of EGFR, with excellent activity against the T790M resistance double mutants and initial single activating mutants. Using an optimization strategy focused on structure-based design and improving PK properties through metabolite identification, we obtained advanced leads with high oral exposure.


Journal of Medicinal Chemistry | 2018

Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances

Marian C. Bryan; Naomi S. Rajapaksa

Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small molecule kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biology involved in the inflammatory response, the factors that lead to safer small molecule kinase inhibitors, and the availability of selective tool molecules for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small molecule kinase inhibitors and where further work is needed to realize the promise of small molecule kinase inhibitors for patient benefit.


Journal of Medicinal Chemistry | 2016

Correction to Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Robert Heald; Krista K. Bowman; Marian C. Bryan; Daniel J. Burdick; Bryan K. Chan; Emily Chan; Yuan Chen; Saundra Clausen; Belen Dominguez-Fernandez; Charles Eigenbrot; Richard L. Elliott; Emily J. Hanan; Philip Stephen Jackson; Hank La; Michael Lainchbury; Shiva Malek; Sam Mann; Mark Merchant; Kyle Mortara; Hans E. Purkey; Gabriele Schaefer; Stephen Schmidt; Eileen Mary Seward; Steve Sideris; Lily Shao; Shumei Wang; Kuen Yeap; Ivana Yen; Christine Yu; Timothy P. Heffron

Robert Heald,* Krista K. Bowman, Marian C. Bryan, Daniel Burdick, Bryan Chan, Emily Chan, Yuan Chen, Saundra Clausen, Belen Dominguez-Fernandez, Charles Eigenbrot, Richard Elliott, Emily J. Hanan, Philip Jackson, Jamie Knight, Hank La, Michael Lainchbury, Shiva Malek, Sam Mann, Mark Merchant, Kyle Mortara, Hans Purkey, Gabriele Schaefer, Stephen Schmidt, Eileen Seward, Steve Sideris, Lily Shao, Shumei Wang, Kuen Yeap, Ivana Yen, Christine Yu, and Timothy P. Heffron

Collaboration


Dive into the Marian C. Bryan's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Hans E. Purkey

Scripps Research Institute

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Michael Lainchbury

Institute of Cancer Research

View shared research outputs
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge