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Jeffrey J Wallin,
Kyle A Edgar,
Jane Guan,
Megan Berry,
Wei Wei Prior,
Leslie Lee,
John D Lesnick,
Cristina Lewis,
Jim Nonomiya,
Jodie Pang, [......],
Carol O'Brien,
Jill M Spoerke,
Sonal Patel,
Letitia Lensun,
Robert Kassees,
Leanne Ross,
Mark R Lackner,
Deepak Sampath,
Marcia Belvin,
Lori S Friedman
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ABSTRACT: Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic.
Molecular Cancer Therapeutics 12/2011; 10(12):2426-36. · 5.23 Impact Factor
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Timothy P Heffron,
Binqing Wei,
Alan Olivero,
Steven T Staben,
Vickie Tsui,
Steven Do,
Jennafer Dotson,
Adrian J Folkes,
Paul Goldsmith,
Richard Goldsmith, [......],
John Lesnick,
Cristina Lewis,
Simon Mathieu,
Jim Nonomiya,
Stephen Shuttleworth, Daniel P Sutherlin,
Nan Chi Wan,
Shumei Wang,
Christian Wiesmann,
Bing-Yan Zhu
[show abstract]
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ABSTRACT: Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.
Journal of Medicinal Chemistry 11/2011; 54(22):7815-33. · 4.80 Impact Factor
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Daniel P Sutherlin,
Linda Bao,
Megan Berry,
Georgette Castanedo,
Irina Chuckowree,
Jenna Dotson,
Adrian Folks,
Lori Friedman,
Richard Goldsmith,
Janet Gunzner, [......],
Deepak Sampath,
Qingping Tian,
Vickie Tsui,
Nan Chi Wan,
Shumei Wang,
Binqing Wei,
Christian Wiesmann,
Ping Wu,
Bing-Yan Zhu,
Alan Olivero
[show abstract]
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ABSTRACT: The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.
Journal of Medicinal Chemistry 11/2011; 54(21):7579-87. · 4.80 Impact Factor
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Steven T Staben,
Michael Siu,
Richard Goldsmith,
Alan G Olivero,
Steven Do,
Daniel J Burdick,
Timothy P Heffron,
Jenna Dotson, Daniel P Sutherlin,
Bing-Yan Zhu, [......],
Jeremy M Murray,
Jim Nonomiya,
Jodie Pang,
Wei Wei Prior,
Laurent Salphati,
Lionel Rouge,
Deepak Sampath,
Steve Sideris,
Christian Wiesmann,
Ping Wu
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ABSTRACT: Starting from thienobenzopyran HTS hit 1, co-crystallization, molecular modeling and metabolic analysis were used to design potent and metabolically stable inhibitors of PI3-kinase. Compound 15 demonstrated PI3K pathway suppression in a mouse MCF7 xenograft model.
Bioorganic & medicinal chemistry letters 07/2011; 21(13):4054-8. · 2.65 Impact Factor
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Steven T Staben,
Timothy P Heffron, Daniel P Sutherlin,
Seema R Bhat,
Georgette M Castanedo,
Irina S Chuckowree,
Jenna Dotson,
Adrian J Folkes,
Lori S Friedman,
Leslie Lee, [......],
Wei Wei Prior,
Laurent Salphati,
Lionel Rouge,
Deepak Sampath,
Vickie Tsui,
Nan Chi Wan,
Shumei Wang,
Christian Weismann,
Ping Wu,
Bing-Yan Zhu
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ABSTRACT: Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.
Bioorganic & medicinal chemistry letters 10/2010; 20(20):6048-51. · 2.65 Impact Factor
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Georgette M Castanedo,
Shumei Wang,
Kirk D Robarge,
Elizabeth Blackwood,
Daniel Burdick,
Christine Chang,
Gerrit J P Dijkgraaf,
Stephen Gould,
Janet Gunzner,
Oivin Guichert, [......],
Cyrus Khojasteh,
Leslie Lee,
James C Marsters,
Lesley Murray,
David Peterson,
Emile Plise,
Laurent Salphati,
Frederic J de Sauvage,
Susan Wong, Daniel P Sutherlin
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ABSTRACT: Potent and efficacious inhibitors of the hedgehog pathway for the treatment of cancer have been prepared using the 2-pyridyl biphenyl amide scaffold common to the clinical lead GDC-0449. Analogs with polar groups in the para-position of the aryl amide ring optimized potency, had minimal CYP inhibition, and possessed good exposure in rats. Compounds 9d and 14f potently inhibited hedgehog signaling as measured by Gli1 mRNA and were found to be equivalent or more potent than GDC-0449, respectively, when studied in a Ptch(+/-) medulloblastoma allograft model, that is, highly dependent on hedgehog signaling.
Bioorganic & medicinal chemistry letters 09/2010; 20(22):6748-53. · 2.65 Impact Factor
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Timothy P Heffron,
Megan Berry,
Georgette Castanedo,
Christine Chang,
Irina Chuckowree,
Jennafer Dotson,
Adrian Folkes,
Janet Gunzner,
John D Lesnick,
Cristina Lewis, [......],
David Peterson,
Laurent Salphati,
Deepak Sampath,
Steve Sideris, Daniel P Sutherlin,
Vickie Tsui,
Nan Chi Wan,
Shumei Wang,
Susan Wong,
Bing-Yan Zhu
[show abstract]
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ABSTRACT: Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.
Bioorganic & medicinal chemistry letters 03/2010; 20(8):2408-11. · 2.65 Impact Factor
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Daniel P Sutherlin,
Deepak Sampath,
Megan Berry,
Georgette Castanedo,
Zhigang Chang,
Irina Chuckowree,
Jenna Dotson,
Adrian Folkes,
Lori Friedman,
Richard Goldsmith, [......],
Wei Wei Prior,
Laurent Salphati,
Steve Sideris,
Qingping Tian,
Vickie Tsui,
Nan Chi Wan,
Shumei Wang,
Christian Wiesmann,
Susan Wong,
Bing-Yan Zhu
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ABSTRACT: The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.
Journal of Medicinal Chemistry 02/2010; 53(3):1086-97. · 4.80 Impact Factor
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Kirk D Robarge,
Shirley A Brunton,
Georgette M Castanedo,
Yong Cui,
Michael S Dina,
Richard Goldsmith,
Stephen E Gould,
Oivin Guichert,
Janet L Gunzner,
Jason Halladay, [......],
Changgeng Qian,
Lee L Rubin,
Laurent Salphati,
Mark S Stanley,
John H A Stibbard, Daniel P Sutherlin,
Savita Ubhayaker,
Shumei Wang,
Susan Wong,
Minli Xie
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ABSTRACT: SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Bioorganic & medicinal chemistry letters 09/2009; 19(19):5576-81. · 2.65 Impact Factor
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Alan G Olivero,
Charles Eigenbrot,
Richard Goldsmith,
Kirk Robarge,
Dean R Artis,
John Flygare,
Thomas Rawson, Daniel P Sutherlin,
Saloumeh Kadkhodayan,
Maureen Beresini,
Linda O Elliott,
Geralyn G DeGuzman,
David W Banner,
Mark Ultsch,
Ulla Marzec,
Stephen R Hanson,
Canio Refino,
Stuart Bunting,
Daniel Kirchhofer
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ABSTRACT: The serine protease factor VIIa (FVIIa) in complex with its cellular cofactor tissue factor (TF) initiates the blood coagulation reactions. TF.FVIIa is also implicated in thrombosis-related disorders and constitutes an appealing therapeutic target for treatment of cardiovascular diseases. To this end, we generated the FVIIa active site inhibitor G17905, which displayed great potency toward TF.FVIIa (Ki = 0.35 +/- 0.11 nM). G17905 did not appreciably inhibit 12 of the 14 examined trypsin-like serine proteases, consistent with its TF.FVIIa-specific activity in clotting assays. The crystal structure of the FVIIa.G17905 complex provides insight into the molecular basis of the high selectivity. It shows that, compared with other serine proteases, FVIIa is uniquely equipped to accommodate conformational disturbances in the Gln217-Gly219 region caused by the ortho-hydroxy group of the inhibitor's aminobenzamidine moiety located in the S1 recognition pocket. Moreover, the structure revealed a novel, nonstandard conformation of FVIIa active site in the region of the oxyanion hole, a "flipped" Lys192-Gly193 peptide bond. Macromolecular substrate activation assays demonstrated that G17905 is a noncompetitive, slow-binding inhibitor. Nevertheless, G17905 effectively inhibited thrombus formation in a baboon arterio-venous shunt model, reducing platelet and fibrin deposition by approximately 70% at 0.4 mg/kg + 0.1 mg/kg/min infusion. Therefore, the in vitro potency of G17905, characterized by slow binding kinetics, correlated with efficacious antithrombotic activity in vivo.
Journal of Biological Chemistry 04/2005; 280(10):9160-9. · 4.77 Impact Factor
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Georgette M Castanedo,
Fredrick C Sailes,
Nathan J P Dubree,
John B Nicholas,
Lisa Caris,
Kevin Clark,
Susan M Keating,
Maureen H Beresini,
Henry Chiu,
Sherman Fong,
James C Marsters,
David Y Jackson, Daniel P Sutherlin
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ABSTRACT: Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.
Bioorganic & Medicinal Chemistry Letters 11/2002; 12(20):2913-7. · 2.55 Impact Factor
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Tetrahedron Letters 42(41):7181-7184. · 2.68 Impact Factor
