TG-1701 A NOVEL, ORALLY AVAILABLE, AND COVALENTLY-BOUND BTK INHIBITOR
Author(s): ,
Emmanuel Normant, PhD
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
,
Leonid Gorelik, PhD
Affiliations:
Fortress Biotech,New York, NY,United States
,
Rama Shmeis, PhD
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
,
Henry Le, MS
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
,
Robert Nisch
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
,
Hari P. Miskin, MS
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
,
Peter Sportelli
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
Michael S. Weiss
Affiliations:
TG Therapeutics, Inc.,New York, NY,United States
(Abstract release date: 05/17/18) EHA Library. Normant, PhD E. 06/15/18; 215080; PF638
Emmanuel Normant, PhD
Emmanuel Normant, PhD
Contributions
Abstract

Abstract: PF638

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Targeting Bruton's tyrosine kinase (BTK), an essential component of the BCR signaling pathway, has been demonstrated to be an effective treatment option for B-cell lymphomas and autoimmune diseases.  However, new BTK inhibitors are needed to allow for better safety and efficacy as a single agent and in combination with other agents.

Aims
Herein we present TG-1701, a novel, orally available and covalently-bound BTK inhibitor that exhibits unique pharmacologic properties compared to prior BTK inhibitors. 

Methods
TG-1701 was evaluated and compared to ibrutinib and/or acalabrutinib in numerous enzyme based, cell-based, and animal models

Results
TG-1701 and ibrutinib have comparable IC50s against BTK (3 nM and 1 nM respectively). TG-1701 exhibits superior selectivity to BTK compared to ibrutinib in in vitro whole kinome screening (DiscoverX, San Diego, CA):

IC50 (nM)

BTK

HER2

ITK

HER4

CSK

EGFR

TG-1701

3

> 3000

> 3000

147

347

270

ibrutinib

1

36

62

4

57

2

In addition, TG-1701 is 61-fold less active on EGFR compared to BTK with a Kd of 270 nM and 4.4 nM respectively. Ibrutinib, however, is only 6.7-fold less active on EGFR compared to BTK with a Kd of 2 nM and 0.3 nM respectively. TG-1701 inhibited the growth of the follicular lymphoma DOHH-2, mantle cell lymphoma Mino and DLBCL SU-DHL-6 cell lines with GI50% of 369, 449 and 313 nM respectively. TG-1701 inhibited IgM-activated BCR pathway in DOHH-2 cells, in particular the phosphorylation of BTK, PLCy2 and ERK1/2. In a cell-based assay, TG-1701 blocked IgM-dependent CD69 expression, adhesion of JEKO cells to VCAM-1, and CXCL12-dependent migration. A fluorescent BTK-occupancy assay was developed and validated in vivo, in the spleen of mice, where BTK was found to be completely occupied after administration of a single dose of TG-1701 at 12.5 mg/kg. In vivo, the anti-tumor efficacy of TG-1701 was assessed in several lymphoma xenograft models, e.g. SU-DHL-6, Mino, and OCI-Ly10 ABC-DLBCL, where TG-1701 showed potent anti-tumor activity equivalent to or greater than ibrutinib and similar to the recently approved BTK inhibitor, acalabrutinib. In addition, the pharmacodynamic profile of TG-1701 allows for a once a day dosing. 

Conclusion
TG-1701 is a novel and highly-selective, irreversible BTK inhibitor with potent in vitro and in vivo activity. TG-1701 is currently being tested in a phase 1 dose escalation study.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): Chronic Lymphocytic Leukemia, NHL

Abstract: PF638

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Targeting Bruton's tyrosine kinase (BTK), an essential component of the BCR signaling pathway, has been demonstrated to be an effective treatment option for B-cell lymphomas and autoimmune diseases.  However, new BTK inhibitors are needed to allow for better safety and efficacy as a single agent and in combination with other agents.

Aims
Herein we present TG-1701, a novel, orally available and covalently-bound BTK inhibitor that exhibits unique pharmacologic properties compared to prior BTK inhibitors. 

Methods
TG-1701 was evaluated and compared to ibrutinib and/or acalabrutinib in numerous enzyme based, cell-based, and animal models

Results
TG-1701 and ibrutinib have comparable IC50s against BTK (3 nM and 1 nM respectively). TG-1701 exhibits superior selectivity to BTK compared to ibrutinib in in vitro whole kinome screening (DiscoverX, San Diego, CA):

IC50 (nM)

BTK

HER2

ITK

HER4

CSK

EGFR

TG-1701

3

> 3000

> 3000

147

347

270

ibrutinib

1

36

62

4

57

2

In addition, TG-1701 is 61-fold less active on EGFR compared to BTK with a Kd of 270 nM and 4.4 nM respectively. Ibrutinib, however, is only 6.7-fold less active on EGFR compared to BTK with a Kd of 2 nM and 0.3 nM respectively. TG-1701 inhibited the growth of the follicular lymphoma DOHH-2, mantle cell lymphoma Mino and DLBCL SU-DHL-6 cell lines with GI50% of 369, 449 and 313 nM respectively. TG-1701 inhibited IgM-activated BCR pathway in DOHH-2 cells, in particular the phosphorylation of BTK, PLCy2 and ERK1/2. In a cell-based assay, TG-1701 blocked IgM-dependent CD69 expression, adhesion of JEKO cells to VCAM-1, and CXCL12-dependent migration. A fluorescent BTK-occupancy assay was developed and validated in vivo, in the spleen of mice, where BTK was found to be completely occupied after administration of a single dose of TG-1701 at 12.5 mg/kg. In vivo, the anti-tumor efficacy of TG-1701 was assessed in several lymphoma xenograft models, e.g. SU-DHL-6, Mino, and OCI-Ly10 ABC-DLBCL, where TG-1701 showed potent anti-tumor activity equivalent to or greater than ibrutinib and similar to the recently approved BTK inhibitor, acalabrutinib. In addition, the pharmacodynamic profile of TG-1701 allows for a once a day dosing. 

Conclusion
TG-1701 is a novel and highly-selective, irreversible BTK inhibitor with potent in vitro and in vivo activity. TG-1701 is currently being tested in a phase 1 dose escalation study.

Session topic: 19. Non-Hodgkin lymphoma Biology & Translational Research

Keyword(s): Chronic Lymphocytic Leukemia, NHL

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies