GSK 2636771

Company: GlaxoSmithKline
Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial
Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.
Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown) is the tris salt of GSK2636771.
Status in the pipeline: Phase I clinical trials……….http://cenblog.org/the-haystack/2012/03/liveblogging-first-time-disclosures-from-acssandiego/

CARMEN

Posted By Carmen Drahl on Mar 24, 2012

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

1372540-25-4

1H-Benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-

2-Methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid

GSK2636771 is a potent, orally bioavailable, PI3Kβ-selective inhibitor, sensitive to PTEN null cell lines.

Formula:C₂₂H_22F3N₃O₃
M.Wt:433.43

WO 2014158467

http://www.google.com/patents/WO2014158467A1?cl=en

According to another embodiment, the invention relates to a method of re- sensitizing BRAF inhibitor resistant melanoma brain metastases comprising the administration of a therapeutically effective amount of

(i) a compound of formula (I)

or a pharmaceutically acceptable salt thereof;

……………………………………………………………….

http://www.google.co.in/patents/WO2014108837A1?cl=en

A combination comprising:

(i) a compound of Structure (I):

or a pharmaceutically acceptable salt thereof;

………………………………………………

SYNTHESIS

GSK 2636771

………………………………………………

WO2012047538

http://www.google.com/patents/WO2012047538A1?cl=en

Example 26

Preparation of methyl 2-methyl-6-(4-morpholinyl)-l-(l-naphthalenylmethyl)-lH- benzimidazole-4-carboxylate a) 3-amino-5-chloro-2-nitrobenzoic acid

Under nitrogen, to a solution of t-BuOK (156.8 g) and Cu(OAc)₂ (3.6 g) in DMF (1.2 L) was added a solution of 5-chloro-2-nitrobenzoic acid (40.0 g) and MeONH₂ HCl (33.2 g) in DMF (300 mL) at 0° C. After 3h the reaction was quenched by addition of H₂0 (2.5 L) and acidified with 10% HC1 solution to pH= 1.The mixture was extracted with EA (2 L x 2) and the combined organic layers were then washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in- vacuo to afford the crude product as a yellow solid (43.2g, yield 100%). 1H NMR (300 MHz, CDC1₃): δ ppm 6.88 (s, 1H, J= 2.4Hz), 6.91 (d, 1H, J= 2.4Hz), 8.08 (br s, 2H); LC-MS: m/e = 217 [M+l]⁺. b) methyl 3-amino-5-chloro-2-nitrobenzoate

A mixture of 3-amino-5-chloro-2-nitrobenzoic acid (43.2 g) and HATU (2-(lH-7- Azabenzotriazol-l-yl)~l,l,3,3-tetramethyl uronium hexafluorophosphate Methanaminium, commercially available) (76 g) in MeOH (81 mL), Et₃N (83 mL) and THF (300 mL) was stirred at room temperature for 3h. When TLC showed no starting material, the solvent was removed in-vacuo and the residue was then diluted with EtOAc (2 L). It was then washed with brine (1 L><3) and dried over anhydrous Na₂S0₄, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc : petroleum ether = 1 : 8 to afford the desired product as a yellow solid (29.5 g, yield 64%). 1H NMR (300 MHz, CDC1₃): δ ppm 3.90 (s, 3H, s), 5.85 (br s, 2H), 6.80 (d, 1H, J = 2.4 Hz), 6.90 (d, 1H, J = 2.4 Hz); LC-MS: m/e = 231 [M+l]⁺ . c) methyl 3-amino-5-(4-morpholinyl)-2-nitrobenzoate

A mixture of combined batches of methyl 3-amino-5-chloro-2-nitrobenzoate (39 g), morpholine (29.5 g) and K₂C0₃ (47 g) was stirred in DMF (200ml) at 110 ⁰ C for 5 h. The mixture was cooled to room temperature and poured into water (1 L). It was extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in-vacuo to afford the desired product as a yellow solid (22 g, yield 46%). 1H NMR (300 MHz, CDC1₃): δ ppm 3.31 (t, 4H, J= 4.8 Hz), 3.82 (t, 4H, J= 4.8 Hz), 3.89 (s, 3H), 6.03 (d, 1H, J= 2.4 Hz), 6.34 (d, 1H, J= 2.4 Hz); LC- MS: m/e = 282 [M+l]⁺ . d) methyl 2-methyl-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate

To a solution of methyl 3-amino-5-(4-morpholinyl)-2-nitrobenzoate (22 g) stirring at reflux in HOAc (400 mL) was added iron powder in portions (13 g). After the addition, the mixture was stirred at reflux for 5 h. It was cooled to room temperature and the solvent was removed in- vacuo. The residue was neutralized with aqueous Na₂C03 solution (1 L). It was extracted with EtOAc (500 mL x3). The combined organic layers were then concentrated in-vacuo and the residue was purified by silica gel chromatography eluted with MeOH : DCM = 1 : 30 to afford the desired product as a solid (16.6 g, yield 77%).

1H NMR (300 MHz, CDC1₃): δ ppm 2.67 (s, 3H), 3.17 (t, 4H, J= 4.8 Hz), 3.90 (t, 4H, J= 4.8 Hz), 3.98 (s, 3H), 7.44 (d, IH, J= 1.8 Hz), 7.54 (d, IH, J= 1.8 Hz);

LC-MS: m/e = 276 [M+l]⁺ .

Example 30

Preparation of methyl 2-methyl-l- {r2-methyl-3-(trifluoromethyl)phenyl1methyl|-6-(4- morpholinyl)- 1 H-benzimidazole-4-carboxylate

A solution of methyl 2-methyl-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate prepared as described in Example 26

methyl 2-methyl-5-(4-morpholinyl)-lH-benzimidazole-7-carboxylate

, step d (500mg, 1.8 mmol), l-(bromomethyl)-2-methyl-3- (trifluoromethyl)benzene (483 mg, 1.9 mmol)

l-(bromomethyl)-2-methyl-3- (trifluoromethyl)benzene

and K₂C0₃ (497 mg, 3.6 mmol) in DMF (50 mL) was stirred at 80° C for 3 h. The reaction mixture was cooled to rt and poured into water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM : MeOH = 50 : 1 to give the crude product IE METHYL ESTER (230 mg, yield 29%), as a white solid.

1H NMR (300 MHz, DMSO-d₆): δ ppm 2.39 (s, 3H), 2.54 (s, 3H), 3.08 (t, 4H, J=4.8 Hz), 3.72 (t, 4H, J=4.8 Hz), 3.89 (s, 3H), 5.57 (s, 2H), 6.27 (d, IH, J=7.5 Hz), 7.22 (t, IH, J=7.5 Hz), 7.27 (d, IH, J=2.4 Hz), 7.38 (d, IH, J=2.4 Hz) 7.60 (d, IH, J=7.5 Hz);

LC-MS: m/e = 448 [M+l]⁺

Example 31

Preparation of 2-methyl- 1 – { [2-methyl-3-(trifluoromethyl)phenyllmethyl| -6-(4-morpholiny0- 1 H-benzimidazole-4-carboxylic acidAn aqueous solution of 2 N LiOH (1.2 mL) was added to a solution of methyl 2-methyl- 1- {[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-lH-benzimidazole-4- carboxylate, prepared as described in Example 30 (180 mg, 0.4 mmol) in THF (10 mL) and stirred at 50° C for 1 h. When TLC showed no starting material remaining, the mixture was cooled to rt and THF was removed under reduced pressure. The pH of the mixture was acidified to pH 3. The suspension was filtered and the filtrate was collected, and washed with water (lOmL) to give the product as a white solid (152 mg, yield 88%).

1H NMR (300 MHz,DMSO-d₆):

δ ppm 2.46 (s, 3H), 2.54 (s, 3H), 3.10 (t, 4H, J=4.8 Hz), 3.73 (t, 4H, J=4.8 Hz), 5.63 (s, 2H), 6.37 (d, IH, J=7.8 Hz), 7.26 (t, IH, J=7.8 Hz), 7.35 (d, IH, J=2.4 Hz), 7.44 (d, IH, J=2.4 Hz), 7.62 (d, IH, J=7.8 Hz);

LC-MS: m/e = 434 [M+l]

WO2010006225A1 *	10 Jul 2009	14 Jan 2010	Novartis Ag	Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of ras/raf/mek pathway
WO2011038380A2 *	28 Sep 2010	31 Mar 2011	Glaxosmithkline Llc	Combination
WO2012061683A2 *	4 Nov 2011	10 May 2012	Glaxosmithkline Llc	Methods for treating cancer
US20120088767 *	3 Oct 2011	12 Apr 2012	Junya Qu	Benzimidazole derivatives as pi3 kinase inhibitors

O2013019620A2 *	Jul 27, 2012	Feb 7, 2013	Glaxosmithkline Llc	Method of treating cancer using combination of braf inhibitor, mek inhibitor, and anti-ctla-4 antibody
US20120202822 *	Oct 12, 2010	Aug 9, 2012	Kurtis Earl Bachman	Combination

CARMEN DRAHL

Links

Phone: 202-872-4502

Fax: 202-872-8727 or -6381

Carmen Drahl

Award-winning science communicator and social media power user based in Washington, DC.

Specialties: interviewing, science writing, social media, Twitter, Storify, YouTube, public speaking, hosting, video production, iPhone videography, non-linear video editing, blogging (WordPress and Blogger), HTML website coding

Education

Princeton University

Ph.D., Chemistry

2002 – 2007

Ph.D. with Erik J. Sorensen
She was on a team that completed the first total synthesis of abyssomicin C, a molecule found in small quantities in nature that showed hints of promise as a potential antibiotic. I constructed molecular probes from abyssomicin for proteomics studies of its biological activity.

M.A. with George L. McLendon
worked toward developing a drug conjugate as a potential treatment for cancer. I synthesized a photosensitizer dye-peptide conjugate for targeting the cell death pathway called apoptosis.

At a reception before the Alumni Day luncheon, President Tilghman (third from left) congratulated the winners of the University’s highest awards for students: (from left) Pyne Prize winners Lester Mackey and Alisha Holland; and Jacobus Fellowship recipients Sarah Pourciau, Egemen Kolemen and Carmen Drahl. Unable to attend the event was Jacobus Fellowship winner William Slauter. (photo: Denise Applewhite

Drew University

B.A., Chemistry

1998 – 2002

Graduated summa cum laude with specialized honors in chemistry. Honors thesis entitled “Structural, kinetic, and mechanistic studies: the protein tyrosine phosphatases CD45 and PTP1B”

Activities and Societies: Phi Beta Kappa

Carmen Drahl, Class of 2002,

Experience

Science Journalist

Freelance

January 2014 – Present Washington D.C. Metro Area

Multimedia science journalist – I deliver clean products on time. Experience in reporting on chemistry, food science, history of science, drug development, science education.

Senior Editor, Chemical & Engineering News

American Chemical Society

August 2007 – December 2014 (7 years 5 months)Washington D.C. Metro Area

Reporting:
Cover the science of chemistry for C&EN, the American Chemical Society’s weekly magazine, circulation 160,000. Track new research findings daily, particularly in forensic science, drug discovery, organic chemistry, and food science.

Video:
Doubled circulation to C&EN’s YouTube channel in 2013. Scripted, narrated, edited footage.
Managed a core team of 4 and collaborated with other reporters to produce 30 videos, some reproduced in The Atlantic, Scientific American, Eater National, The Daily Mail.

Incepted, scripted, and co-hosted “Speaking of Chemistry”, a monthly web show that summarizes top chemistry news for the busy scientist.

Social Media:
Developed magazine-wide best practices for YouTube videos and Twitter. Ran staff workshops about Storify, Slashdot, and Reddit.

Hosting/Public Speaking:
Topics include communicating chemistry simply, transitioning from a Ph.D. to careers in science communication. Moderated discussions on chemophobia, social media usage in the chemical sciences. On-camera co-host for web newscasts produced by ACS.

Innovation:
With C&EN art and web teams, developed first-for-the-magazine features, including a 90th anniversary commemorative timeline poster, a pullout guide to top conference speakers, interactive quizzes and database searches.

Carmen Drahl, senior editor of Chemical and Engineering News, used her Ph.D. in chemistry as a springboard into the career she envisioned for herself. Here she shares some advice that helped her make the decision.

Carmen Drahl made the transition to a writing career while earning a Ph.D. in chemistry at Princeton University. Born and raised in New Jersey, she now lives in Washington, D.C., and reports for Chemical and Engineering News (C&EN). At C&EN she has written about how new medications get their names, explained the science behind a controversial hair-straightening product, and covered the scientific firestorm sparked by an alleged arsenic life form. Her work has been featured on SiriusXM’s Doctor Radio, Radio New Zealand’s This Way Up, and elsewhere. Her coverage has also been recognized by MIT’s Knight Science Journalism Tracker.

(Open)1 honor or award

Scientific Cocktails: Award-winning video

Speaking of Chemistry: All About Tinsel

Carmen Drahl

Twitter Maven

World Central Kitchen

March 2013 – August 2014 (1 year 6 months)Washington D.C. Metro Area

I was the “voice of Twitter” for World Central Kitchen, the humanitarian organization founded by renowned Chef José Andrés. Doubled followers to Twitter account in 2013, developed Twitter strategy for projects and events. Edited Annual Report, press releases and other communication materials. Volunteered in person at outreach events.

Contributing Editor, AWIS Magazine

Association of Women in Science

December 2005 – August 2007 (1 year 9 months)

sHE reported and wrote profiles of prominent women scientists in a range of fields (molecular biology, physics, geoscience) for the Research Advances column in AWIS Magazine.

Writer, various publications

Princeton University

April 2005 – May 2007 (2 years 2 months)

She reported and wrote news for the Princeton University News Office’s Research Notes, and wrote news and features for the Princeton University Chemistry Department’s Industrial Affiliates Program Newsletter and Chemistry Alumni Newsletter.

Honors & Awards

Eddie Digital Award- Best Video (B-to-B)

FOLIO Magazine

December 2014

Porter Ogden Jacobus Fellowship

Princeton University

February 2007

NSF Graduate Research Fellowship

National Science Foundation

2002

Volunteer Experience & Causes

Board Member

Princeton Alumni Weekly Magazine

October 2013

Advisory Committee

American Institute of Physics News and Media Services

October 2013

Member, Graduate Alumni Leadership Council

Princeton University

2009 – 2012 (3 years)

INTERVIEW

http://scienceblogs.com/clock/2010/04/12/scienceonline2010-interview-33/

Continuing with the tradition from last two years, I will occasionally post interviews with some of the participants of the ScienceOnline2010 conference that was held in the Research Triangle Park, NC back in January. See all the interviews in this series here. You can check out previous years’ interviews as well: 2008 and 2009.

Today, I asked Carmen Drahl, Associate Editor for Science/Technology/Education at Chemical & Engineering News (find her as @carmendrahl on Twitter) to answer a few questions.

Welcome to A Blog Around The Clock. Would you, please, tell my readers a little bit more about yourself? Where are you coming from (both geographically and philosophically)? What is your (scientific) background?

i-b183f89fe33d3d9f0b308a6cb30d9b5b-Carmen Drahl pic1.JPG It’s a pleasure and a privilege to be interviewed, Bora.

Good conversations make me happy. School was fun for me (well, maybe not grad school) and that’s evolved into a desire to always be learning something new. I enjoy doing nothing as much as I enjoy doing things. On Mondays, if I’m not too busy, I take hip-hop dance classes.

My hometown is Hackettstown, New Jersey. M&M’s are made there. I got a bachelor’s in chemistry from Drew University and a Ph.D. in chemistry at Princeton. Scientifically my expertise hovers somewhere around the interface between organic chemistry and biochemistry. A short while after defending my dissertation, I moved to Washington DC to write for Chemical & Engineering News, and that’s where I’ve been for almost three years now.

When and how did you first discover science blogs?

Scandal led me to science blogs. Seriously. In March 2006 I was still an organic chemistry grad student. Everyone in my lab was buzzing about a set of retractions in the Journal of the American Chemical Society (disclosure: today I work for the American Chemical Society, which publishes JACS). A rising young organic chemistry star retracted the papers because work by one of his graduate students couldn’t be reproduced. It was a big deal and became an even bigger deal as the inevitable rumors (salacious and otherwise) surfaced. The blogosphere had the details first. So that’s where Google pointed me and the other members of my lab when we searched for more information. I learned about the awesome (but sadly now defunct) blogs Tenderbutton and The Endless Frontier, by Dylan Stiles and Paul Bracher, both chemistry grad students like me. I also discovered the solid mix of chemistry and pharma at Derek Lowe’s In the Pipeline, which is still the first blog I visit every day.

Tell us a little more about your career trajectory so far: interesting projects past and present?

i-b7bd4d4568d9689c2daf400303c886c3-Carmen Drahl pic2.JPG By the time I discovered science blogs I knew my career goals were changing. I’d already been lucky enough to audit a science writing course at Princeton taught by Mike Lemonick from TIME, and thought that maybe science writing was a good choice for me. After reading chemistry blogs for a while I realized “Hey, I can do this!” and started my own blog, She Blinded Me with Science, in July 2006. It was the typical grad student blog, a mix of posts about papers I liked and life in the lab.

At C&E News I’ve contributed to its C&ENtral Science blog, which premiered in spring 2008. I’ve experimented with a few different kinds of posts- observations and on-the-street interviews when I run into something chemistry-related in DC, in-depth posts from meetings, and video demos of iPod apps. One of my favorite things to do is toy with new audio/video/etc technology for the blog.

What is taking up the most of your time and passion these days? What are your goals?

In March I just started a new era in my web existence- I’m becoming a pharma blogger. I’m the science voice at The Haystack, C&E News’s new pharma blog and one of seven new blogs the magazine launched last month. My co-blogger is the talented Lisa Jarvis, who’s written about the business side of pharma for ten years and who brings a solid science background to the table as well. I kicked us off by liveblogging/livetweeting a popular session at the American Chemical Society’s meeting in San Francisco where drug companies reveal for the first time the chemical structures of potential new drugs being tested in clinical trials. The whole thing synced to FriendFeed as well. Folks followed the talks from all three venues, which was great. I hope I can continue doing that sort of thing in the future.

For this August, I’m co-organizing a mini-symposium at the American Chemical Society meeting in Boston about the chem/pharma blogosphere and its impact on research and communication. I’m in the process of inviting speakers right now. It’s my first time doing anything like this and part of me is petrified that no one will show up. Tips on organizing a conference session and how not to stress when doing so are welcome!

More broadly, I’d love to get more chemistry bloggers to connect with the community that attends ScienceOnline. I don’t ever want to become that old (or not-so-old) person who is clueless about them-thar newfangled whosiwhatsits that the kids are using nowadays.

What aspect of science communication and/or particular use of the Web in science interests you the most?

A few things come to mind, actually. I’d like to think that the web has made grad school a helluva lot less isolating for science grad students. You have the virtual journal clubs like Totally Synthetic, posts like SciCurious’s letter to a grad student, etc.

As a journalist the web’s capacity to equalize fascinates me. I’m extremely lucky to have a staff gig as a science writer without having gone to journalism school or landed a media fellowhip and it’s weird to think that my old blog might’ve helped my visibility. I didn’t know Ed Yong’s story until Scio10 but I think he’s a highly talented example of how the web can open doors.

The web’s equalizing power goes to readers of science content as well as writers, of course. In the ideal situation a reader can give a writer instant feedback and you can get a real conversation going, something that was much harder with the snail-paced system of letters to the editor and reader surveys. Not that the conversation is always civil. Most of C&EN’s readers have a decent amount of scientific training, but the debate that rages whenever we run an editorial about climate change is as intense as any I’ve seen.

In cases like that I don’t know that the web gives people a good representation of what the consensus is. For folks who don’t have scientific training, how do you ensure that people don’t just go to the content that already confirms their pre-existing beliefs about autism or global warming? John Timmer touched on this more eloquently in his interview with you, and I agree with him that I don’t think we have an answer yet. Though on a slightly different note, I will mention that I’ve been enjoying the New York Times’s recent attempts to recapture the spontaneity of flipping through the newspaper in online browsing, like the Times Skimmer for Google Chrome.

What are some of your favourite science blogs? Have you discovered any cool science blogs by the participants at the Conference?

In addition to the blogs I’ve already mentioned I enjoy Carbon-Based Curiosities, Wired Science, Chemistry Blog, and Terra Sigillata, to name a few of the 50 or so blogs on my feed reader.

I discovered scads of new blogs at Scio10 but I’ll focus on the one that’s become required reading for me these days: Obesity Panacea. I’d covered obesity drug development for C&EN but I’d never met Travis Saunders and Peter Janiszewski or heard of their blog until the conference.

What was the best aspect of ScienceOnline2010 for you? Is there anything that happened at this Conference – a session, something someone said or did or wrote – that will change the way you think about science communication, or something that you will take with you to your job, blog-reading and blog-writing?

Dave Mungeris my hero – his blogging 102 session was packed with practical tips that I brought back to C&EN for incorporating into our blogs, such as the use of the Disqus plugin for catching conversations on social networks, getting smart about using stats and surveys, etc. Some of that’s already happened, and some of the ideas are still in the works.

I came for the nuts-and-bolts blogging tips but I stayed for the conversations, especially the ones at the bar after the official program was done for the night. And the icing on the cake was seeing folks I’d worked with but never met, like Cameron Neylon and you, Bora, and catching up with people I hadn’t seen in months, like Jean-Claude Bradley, Aaron Rowe, Jennifer Ouellette and Nancy Shute.

It was so nice to meet you in person and thank you for the interview. I hope to see you again next January.