A Phase 1/1b Study of Paclitaxel in Combination With BOS172722, a Monopolar Spindle 1 Kinase Inhibitor, in Patients With Advanced Nonhaematologic Malignancies

This study will be conducted to assess the safety and tolerability of BOS172722 when administered as monotherapy and in combination with paclitaxel in participants with advanced nonhaematologic malignancies and also to establish the maximum tolerated dose and recommended Phase 2 dose of BOS172722 in combination with paclitaxel in those participants.

开始日期2017-10-13

申办/合作机构

Boston Pharmaceuticals, Inc.初创企业

100 项与 BOS-172722 相关的临床结果

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100 项与 BOS-172722 相关的转化医学

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100 项与 BOS-172722 相关的专利（医药）

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项与 BOS-172722 相关的文献（医药）

2019-10-01·Molecular Cancer Therapeutics2区 · 医学

High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers

2区 · 医学

Article

作者: Woodward, Hannah L. ; Linardopoulos, Spiros ; Naud, Sébastien ; Mak, Grace Wing-Yan ; Drosopoulos, Konstantinos ; Theofani, Efthymia ; Saville, Harry ; Anderhub, Simon J. ; Walsh, Katie ; Hoelder, Swen ; Burke, Rosemary ; Westwood, Isaac M. ; Hayes, Angela ; Innocenti, Paolo ; Eccles, Suzanne A. ; Gurden, Mark D. ; Raynaud, Florence I. ; Filosto, Simone ; van Montfort, Rob L.M. ; Faisal, Amir ; Blagg, Julian

AbstractBOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor–mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.

2018-09-27·Journal of Medicinal Chemistry1区 · 医学

Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4-d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N²-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N⁸-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine (BOS172722)

1区 · 医学

Article

作者: van Montfort, Rob L. M. ; Broccatelli, Fabio ; Eccles, Suzanne A. ; Woodward, Hannah L. ; Mak, Grace Wing-Yan ; Henley, Alan T. ; Blagg, Julian ; Roberts, Jennie ; Cheung, Kwai-Ming J. ; Linardopoulos, Spiros ; Cronin, Nora ; O’Fee, Lisa ; Hayes, Angela ; Faisal, Amir ; Raynaud, Florence I. ; Box, Gary ; Valenti, Melanie ; Hoelder, Swen ; Innocenti, Paolo ; Westwood, Isaac M. ; Schmitt, Jessica ; Burke, Rosemary ; Saville, Harry ; Carter, Michael ; De Haven Brandon, Alexis

Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.

100 项与 BOS-172722 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15498

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床1期	英国	The Institute of Cancer Research: Royal Cancer Hospital	2023-01-30
ER阳性乳腺癌	临床前	英国	The Institute of Cancer Research: Royal Cancer Hospital	2018-07-01
肿瘤	药物发现	英国	Boston Pharmaceuticals, Inc.初创企业	2017-10-13