Replies to post #23444 on Ariad Pharmaceuticals Inc fka ARIA

[north40000]

Change of mind---markets closed

http://online.wsj.com/article/SB10001424052970204840504578085041035358414.html?mod=djemalertNEWS

U.S. stock and options markets will close Monday due to Hurricane Sandy, exchanges and regulators said, and there was a chance the markets would remain closed through Tuesday.

Earlier in the day Sunday, exchanges had decided to close their trading floors but stay open for electronic trading. However, exchanges, regulators and trading firms agreed late Sunday to close all U.S. stock markets.

Customers had complained to the exchanges and to the Securities and Exchange Commission that partial closures of the market would be too complicated, according to people with knowledge of the matter.

more

[mejs]

I was correct about the market being Closed and will be correct about ARIA snd a _VS Standstill Agreement by July 2013

[ariadndndough]

don or peter is it possible that one of these compounds at the bottom might be one of ariad next targets?


Liu, S (Shuangying)
Latest papers:
Bioorg Med Chem Lett. 2011 Jun 15;21 (12):3743-8 21561767 Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant.
[My paper] Mathew Thomas, Wei-Sheng Huang, David Wen, Xiaotian Zhu, Yihan Wang, Chester A Metcalf, Shuangying Liu, Ingrid Chen, Jan Romero, Dong Zou, Raji Sundaramoorthi, Feng Li, Jiwei Qi, Lisi Cai, Tianjun Zhou, Lois Commodore, Qihong Xu, Jeff Keats, Frank Wang, Scott Wardwell, Yaoyu Ning, Joseph T Snodgrass, Marc I Broudy, Karin Russian, John Iuliucci, Victor M Rivera, Tomi K Sawyer, David C Dalgarno, Tim Clackson, William C Shakespeare
ARIAD Pharmaceuticals Inc., 26 Lansdowne Street, Cambridge, MA 02139, USA. [e-mail]
Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML. J Med Chem. 2010 Jun 24;53 (12):4701-19 20513156 Cit:4 Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.
[My paper] Wei-Sheng Huang, Chester A Metcalf, Raji Sundaramoorthi, Yihan Wang, Dong Zou, R Mathew Thomas, Xiaotian Zhu, Lisi Cai, David Wen, Shuangying Liu, Jan Romero, Jiwei Qi, Ingrid Chen, Geetha Banda, Scott P Lentini, Sasmita Das, Qihong Xu, Jeff Keats, Frank Wang, Scott Wardwell, Yaoyu Ning, Joseph T Snodgrass, Marc I Broudy, Karin Russian, Tianjun Zhou, Lois Commodore, Narayana I Narasimhan, Qurish K Mohemmad, John Iuliucci, Victor M Rivera, David C Dalgarno, Tomi K Sawyer, Tim Clackson, William C Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. [e-mail]
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies. Most cited papers:
Bioorg Med Chem Lett. 2003 Sep 15;13 (18):3063-6 12941334 Cit:7 Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogues.
[My paper] Raji Sundaramoorthi, William C Shakespeare, Terence P Keenan, Chester A Metcalf 3rd, Yihan Wang, Ukti Mani, Merry Taylor, Shuangying Liu, Regine S Bohacek, Surinder S Narula, David C Dalgarno, Marie Rose van Schravandijk, Sheila M Violette, Shuenn Liou, Susan Adams, Mary K Ram, Jeffrey A Keats, Manfred Weigle, Tomi K Sawyer, Manfred Weigele
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. [e-mail]
Src tyrosine kinase is a therapeutic target for bone diseases that has been validated by gene knockout studies. Furthermore, in vitro cellular studies implicate that Src has a positive regulatory role in osteoclasts and a negative regulatory role in osteoblasts. The potential use of Src inhibitors for osteoporosis therapy has been previously shown by novel bone-targeted ligands of the Src SH2 (e.g., AP22408) and non-bone-targeted, ATP-based inhibitors of Src kinase. Significant to this study, compounds 2-12 exemplify novel analogues of known pyrrolopyrimidine and pyrazolopyrimidine template-based Src kinase inhibitors that incorporate bone-targeting group modifications designed to provide tissue (bone) selectivity and diminished side effects. Accordingly, we report here the structure-based design, synthetic chemistry and biological testing of these compounds and proof-of-concept studies thereof. J Med Chem. 2009 Jul 2;: 19572547 Cit:5 9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation: Design, Synthesis, and Biological Evaluation.
[My paper] Wei-Sheng Huang, Xiaotian Zhu, Yihan Wang, Mohammad Azam, David Wen, Raji Sundaramoorthi, R Mathew Thomas, Shuangying Liu, Geetha Banda, Scott P Lentini, Sasmita Das, Qihong Xu, Jeff Keats, Frank Wang, Scott Wardwell, Yaoyu Ning, Joseph T Snodgrass, Marc I Broudy, Karin Russian, George Q Daley, John Iuliucci, David C Dalgarno, Tim Clackson, Tomi K Sawyer, William C Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139.
A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC(50)= 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia. J Med Chem. 2010 Jun 24;53 (12):4701-19 20513156 Cit:4 Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant.
[My paper] Wei-Sheng Huang, Chester A Metcalf, Raji Sundaramoorthi, Yihan Wang, Dong Zou, R Mathew Thomas, Xiaotian Zhu, Lisi Cai, David Wen, Shuangying Liu, Jan Romero, Jiwei Qi, Ingrid Chen, Geetha Banda, Scott P Lentini, Sasmita Das, Qihong Xu, Jeff Keats, Frank Wang, Scott Wardwell, Yaoyu Ning, Joseph T Snodgrass, Marc I Broudy, Karin Russian, Tianjun Zhou, Lois Commodore, Narayana I Narasimhan, Qurish K Mohemmad, John Iuliucci, Victor M Rivera, David C Dalgarno, Tomi K Sawyer, Tim Clackson, William C Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. [e-mail]
In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies. Chem Biol Drug Des. 2008 Jan 3;: 18179464 Cit:4 SAR of Carbon-Linked, 2-Substituted Purines: Synthesis and Characterization of AP23451 as a novel Bone-Targeted Inhibitor of Src Tyrosine Kinase With In Vivo Anti-Resorptive Activity.
[My paper] William C Shakespeare, Yihan Wang, Regine Bohacek, Terry Keenan, Raji Sundaramoorthi, Chet Metcalf 3rd, Anne Dilauro, Sonya Roeloffzen, Shuangying Liu, Jennifer Saltmarsh, Guru Paramanathan, David Dalgarno, Surinder Narula, Selvi Pradeepan, Marie Rose van Schravendijk, Jeff Keats, Mary Ram, Shuenn Liou, Susan Adams, Scott Wardwell, Julie Bogus, John Iuliucci, Manfred Weigele, Lianping Xing, Brendan Boyce, Tomi K Sawyer
Targeted disruption of the pp60(src)(Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC(50)= 68 nm against Src kinase; an X-ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose-dependent decrease in PTH-induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC(50)= 73 nm) except devoid of the bone-targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds. Bioorg Med Chem Lett. 2008 Jun 18;: 18691885 Cit:3 Novel N(9)-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors.
[My paper] Yihan Wang, William C Shakespeare, Wei-Sheng Huang, Raji Sundaramoorthi, Scott Lentini, Sasmita Das, Shuangying Liu, Geeta Banda, David Wen, Xiaotian Zhu, Qihong Xu, Jeffrey Keats, Frank Wang, Scott Wardwell, Yaoyu Ning, Joseph T Snodgrass, Mark I Broudy, Karin Russian, David Dalgarno, Tim Clackson, Tomi K Sawyer
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA.
Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.