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Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

ABSTRACT: Highly selective PI3K inhibitors with subnanomolar PI3K? potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

SUBMITTER: Liu KK

PROVIDER: S-EPMC4018126 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

Liu Kevin K-C KK Zhu JinJiang J Smith Graham L GL Yin Min-Jean MJ Bailey Simon S Chen Jeffrey H JH Hu Qiyue Q Huang Qinhua Q Li Chunze C Li Qing J QJ Marx Matthew A MA Paderes Genevieve G Richardson Paul F PF Sach Neal W NW Walls Marlena M Wells Peter A PA Baxi Sangita S Zou Aihua A

ACS medicinal chemistry letters 20110919 11

Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communica ...[more]

PMID: 24900269

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

Dataset Information

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

Publications

Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

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