2. Academic Validation
  3. BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models

  • Nat Cancer. 2024 Aug 23. doi: 10.1038/s43018-024-00814-0.
Ulrike Rauh 1,  Guo Wei 2,  Michael Serrano-Wu 3,  Georgios Kosmidis 4,  Stefan Kaulfuss 5,  Franziska Siegel 6,  Kai Thede 5,  James McFarland 2,  Christopher T Lemke 2,  Nicolas Werbeck 6,  Katrin Nowak-Reppel 5,  Sabine Pilari 7,  Stephan Menz 6,  Matthias Ocker 8,  Weiqun Zhang 2,  Kyle Davis 2,  Guillaume Poncet-Montange 2,  Jennifer Roth 2,  Douglas Daniels 8,  Virendar K Kaushik 8,  Brian Hubbard 3,  Karl Ziegelbauer 9,  Todd R Golub 10 11
Affiliations

Affiliations

  • 1 Trueline Therapeutics Inc., Cambridge, MA, USA. ulla@truelinetx.com.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 3 Anji Pharmaceuticals Inc., Cambridge, MA, USA.
  • 4 Ncardia, Leiden, The Netherlands.
  • 5 Nuvisan Innovation Campus Berlin, Berlin, Germany.
  • 6 Bayer AG R&D, Berlin, Germany.
  • 7 Independent Consultant, Pharmacometrics Modeling and Simulation, Berlin, Germany.
  • 8 Trueline Therapeutics Inc., Cambridge, MA, USA.
  • 9 Almirall R&D, Sant Feliu de Llobregat, Spain.
  • 10 Broad Institute of MIT and Harvard, Cambridge, MA, USA. golub@broadinstitute.org.
  • 11 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. golub@broadinstitute.org.
PMID: 39179926 DOI: 10.1038/s43018-024-00814-0
Abstract

The MCL1 gene is frequently amplified in Cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive Anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce Apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162858
    MCL1抑制剂
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