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Dive into the research topics where Mark Merchant is active.

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Featured researches published by Mark Merchant.


Nature Genetics | 1994

A genetic map of the mouse with 4,006 simple sequence length polymorphisms.

William F. Dietrich; Joyce Miller; Robert G. Steen; Mark Merchant; Deborah Damron; Robert Nahf; Alec Gross; Diane C. Joyce; Michael Wessel; Robert Dredge; Andre Marquis; Lincoln Stein; Nathan Goodman; David C. Page; Eric S. Lander

We have constructed a genetic map of the mouse genome containing 4,006 simple sequence length polymorphims (SSLPs). The map provides an average spacing of 0.35 centiMorgans (cM) between markers, corresponding to about 750 kb. Approximately 90% of the genome lies within 1.1 cM of a marker and 99% lies within 2.2 cM. The markers have an average polymorphism rate of 50% in crosses between laboratory strains. The markers are distributed in a relatively uniform fashion across the genome, although some deviations from randomness can be detected. In particular, there is a significant underrepresentation of markers on the X chromosome. This map represents the two–thirds point toward our goal of developing a mouse genetic map containing 6,000 SSLPs.


Nature | 2013

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

Georgia Hatzivassiliou; Jacob R. Haling; Huifen Chen; Kyung Song; Steve Price; Robert Heald; Joanne Frances Mary Hewitt; Mark Zak; Ariana Peck; Christine Orr; Mark Merchant; Klaus P. Hoeflich; Jocelyn Chan; Shiuh-Ming Luoh; Daniel J. Anderson; Mary J. C. Ludlam; Christian Wiesmann; Mark Ultsch; Lori Friedman; Shiva Malek; Marcia Belvin

KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients.


Journal of Medicinal Chemistry | 2016

Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development.

James F. Blake; Michael Burkard; Jocelyn Chan; Huifen Chen; Kang-Jye Chou; Dolores Díaz; Danette Dudley; John J. Gaudino; Stephen E. Gould; Jonas Grina; Thomas Hunsaker; Lichuan Liu; Matthew Martinson; David Moreno; Lars Mueller; Christine Orr; Patricia Pacheco; Ann Qin; Kevin Rasor; Li Ren; Kirk Robarge; Sheerin Shahidi-Latham; Jeffrey Stults; Francis J. Sullivan; Weiru Wang; JianPing Yin; Aihe Zhou; Marcia Belvin; Mark Merchant; John Moffat

The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.


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.


Cancer Research | 2014

Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development

Kirk Robarge; Jacob B. Schwarz; Jim Blake; Michael Burkard; Jocelyn Chan; Huifen Chen; Kang-Jye Chou; John J. Gaudino; Stephen Jay Gould; Jonas Grina; Xin Linghu; Lichuan Liu; Matthew Martinson; David Moreno; Christine Orr; Patricia Pacheco; Ann Qin; Kevin Rasor; Li Ren; Sheerin Shahidi-Latham; Jeffrey Stults; Francis J. Sullivan; Weiru Wang; Peter Yin; Aihe Zhou; Marcia Belvin; Mark Merchant; John Moffat

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The extracellular-signal-regulated kinases (ERK1 and ERK2) represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that commonly is activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling, such as receptor tyrosine kinase (RTK) activation. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Here, we present the discovery and characterization of GDC-0994, an orally bioavailable, small molecule inhibitor of ERK kinase activity. GDC-0994 is highly selective for ERK1 and ERK2, with biochemical potency of 1.1 nM and 0.3 nM, respectively. Daily, oral dosing of GDC-0994 results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice. PD biomarker inhibition of phospho-p90RSK in these tumors correlates with potency in vitro and in vivo. In contrast to other published ERK inhibitors, GDC-0994 neither increases nor decreases phospho-ERK, suggesting that different ERK inhibitors have alternative mechanisms of action with respect to feedback signaling. Furthermore, we demonstrate a novel approach for targeting the oncogenic signaling through the RAS pathway by combining ERK and MEK inhibitors. GDC-0994 is currently in Phase I clinical development. Citation Format: Kirk Robarge, Jacob Schwarz, Jim Blake, Michael Burkard, Jocelyn Chan, Huifen Chen, Kang-Jye Chou, Dolores Diaz, John Gaudino, Stephen Gould, Jonas Grina, Xin Linghu, Lichuan Liu, Matthew Martinson, David A. Moreno, Christine Orr, Patricia Pacheco, Ann Qin, Kevin Rasor, Li Ren, Sheerin Shahidi-Latham, Jeffrey Stults, Francis Sullivan, Weiru Wang, Peter Yin, Aihe Zhou, Marcia Belvin, Mark Merchant, John G. Moffat. Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT02-03. doi:10.1158/1538-7445.AM2014-DDT02-03


Cancer Cell | 2018

Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors

Ivana Yen; Frances Shanahan; Mark Merchant; Christine Orr; Thomas Hunsaker; Matthew Durk; Hank La; Xiaolin Zhang; Scott E. Martin; Eva Lin; John K. Chan; Yihong Yu; Dhara Amin; Richard M. Neve; Amy Gustafson; Avinashnarayan Venkatanarayan; Scott A. Foster; Joachim Rudolph; Christiaan Klijn; Shiva Malek

Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition.


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


Nature | 1996

A comprehensive genetic map of the mouse genome.

William F. Dietrich; Joyce Miller; Robert G. Steen; Mark Merchant; Deborah Damron-Boles; Zeeshan Husain; Robert Dredge; Mark J. Daly; Kimberly A. Ingalls; Tara J. O'Connor; Cheryl A. Evans; Margaret M. DeAngelis; David M. Levinson; Leonid Kruglyak; Nathan Goodman; Neal G. Copeland; Nancy A. Jenkins; Trevor Hawkins; Lincoln Stein; David C. Page; Eric S. Lander


Nature Genetics | 1995

Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice

George T. De Sanctis; Mark Merchant; David R. Beier; Robert Dredge; James K. Grobholz; Thomas R. Martin; Eric S. Lander; Jeffrey M. Drazen


Nature | 1996

Erratum: A comprehensive genetic map of the mouse genome

William F. Dietrich; Joyce Miller; Robert G. Steen; Mark Merchant; Deborah Damron-Boles; Zeeshan Husain; Robert Dredge; Mark J. Daly; Kimberly A. Ingalls; Tara J. O'Connor; Cheryl A. Evans; Margaret M. DeAngelis; David M. Levinson; Nathan Goodman; Neal G. Copeland; Nancy A. Jenkins; Trevor Hawkins; Lincoln Stein; David C. Page; Eric S. Lander

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Robert Dredge

Massachusetts Institute of Technology

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Joyce Miller

Massachusetts Institute of Technology

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Nathan Goodman

Massachusetts Institute of Technology

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Robert G. Steen

Massachusetts Institute of Technology

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