Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

被引：96

作者：

McCoull, William ^{[1
]}

Cheung, Tony ^{[2
]}

Anderson, Erica ^{[2
]}

Barton, Peter ^{[1
]}

Burgess, Jonathan ^{[1
]}

Byth, Kate ^{[2
,5
]}

Cao, Qing ^{[2
,6
]}

Castald, M. Paola ^{[2
]}

Chen, Huawei ^{[2
]}

Chiarparin, Elisabetta ^{[1
]}

Carbajo, Rodrigo J. ^{[1
]}

Code, Erin ^{[2
]}

Cowan, Suzanna ^{[1
,7
]}

Davey, Paul R. ^{[1
]}

Ferguson, Andrew D. ^{[2
]}

Fillery, Shaun ^{[1
]}

Fuller, Nathan O. ^{[2
,8
]}

Gao, Ning ^{[2
]}

Hargreaves, David ^{[1
]}

Howard, Martin R. ^{[1
]}

Hu, Jun ^{[2
,9
]}

Kawatkar, Aarti ^{[2
]}

Kemmitt, Paul D. ^{[1
]}

Leo, Elisabetta ^{[1
]}

Molina, Daniel M. ^{[3
]}

O'Conne', Nichole ^{[2
,10
]}

Petteruti, Philip ^{[2
]}

Rasmusson, Timothy ^{[2
,11
]}

Raubo, Piotr ^{[1
]}

Rawlins, Philip B. ^{[1
]}

Ricchiuto, Piero ^{[1
]}

Robb, Graeme R. ^{[1
]}

Schenone, Monica ^{[4
]}

Waring, Michael J. ^{[1
,12
]}

Zinda, Michael ^{[2
,13
]}

Fawell, Stephen ^{[2
]}

Wilson, David M. ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Oncol & Discovery Sci, 310 Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, England

[2] AstraZeneca, IMED Biotech Unit, Oncol & Discovery Sci, Gatehouse Pk, Waltham, MA 02451 USA

[3] Pelago Biosci AB, Banvaktsvagen 20, S-17148 Solna, Sweden

[4] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA

[5] IFM Therapeut LLC, 855 Boylston St,11th Floor, Boston, MA 02116 USA

[6] Ra Pharmaceut, 87 Cambridge Pk Dr, Cambridge, MA 02140 USA

[7] Astex Pharmaceut, 436 Cambridge Sci Pk,Milton Rd, Cambridge CB4 0QA, England

[8] Rodin Therapeut, 300 Technol Sq,Life Sci Suites, Cambridge, MA 02139 USA

[9] Shire, 300 Shire Way, Lexington, MA 02421 USA

[10] Cedilla Therapeut, 38 Sidney St,Second Floor, Cambridge, MA 02139 USA

[11] Celgene Corp, 200 Cambridge Pk Dr, Cambridge, MA 02140 USA

[12] Newcastle Univ, Sch Chem, Northern Inst Canc Res, Bedson Bldg, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[13] Repare Therapeut USA Inc, 1 Broadway,14th Floor, Cambridge, MA 02142 USA

来源：

ACS CHEMICAL BIOLOGY | 2018年 / 13卷 / 11期

关键词：

DRUG DISCOVERY; N-COR; INHIBITOR; DEGRADATION; EXPRESSION; REPRESSION; ROLES; EZH2;

D O I：

10.1021/acschembio.8b00698

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.

引用

页码：3131 / 3141

页数：11

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