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
  • 1. Trueline Therapeutics Inc., Cambridge, MA, USA. [email protected].
  • 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. [email protected].
  • 11. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. [email protected].
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.

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