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Published on: May 15, 2019
BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and
Ulrike Rauh1, Guo Wei2, Michael Serrano-Wu3
1Trueline Therapeutics Inc., Cambridge, MA, USA. ulla@truelinetx.com.
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.
Insights
BRD-810 is a novel myeloid cell leukemia 1 (MCL1) inhibitor that rapidly kills cancer cells. This MCL1 inhibitor shows efficacy in preclinical models with a potentially favorable safety profile, warranting clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The MCL1 gene is amplified in various cancers, leading to resistance against standard therapies.
- Myeloid cell leukemia 1 (MCL1) is an antiapoptotic protein that promotes cancer cell survival.
- Targeting MCL1 is a promising strategy for developing new anticancer treatments.
Purpose of the Study:
- To introduce BRD-810, a potent and selective MCL1 inhibitor designed for rapid systemic clearance.
- To evaluate the efficacy and safety profile of BRD-810 in preclinical cancer models.
- To assess the potential of short-term MCL1 inhibition for cancer therapy.
Main Methods:
- In vitro assessment of BRD-810's cell-killing effects and cardiomyocyte toxicity.
- In vivo evaluation of BRD-810's anti-tumor efficacy in xenograft hematological and solid tumor models.
- Pharmacokinetic analysis focusing on rapid systemic clearance.
Main Results:
- BRD-810 demonstrated rapid tumor cell killing in vitro within 4 hours.
- BRD-810 showed no impact on cardiomyocyte viability or function at high concentrations in vitro.
- BRD-810 achieved significant anti-tumor efficacy in vivo despite its short plasma residence time.
Conclusions:
- Short-term inhibition of MCL1 with BRD-810 can effectively induce tumor cell apoptosis.
- BRD-810 exhibits a potentially favorable safety profile, particularly concerning cardiac function.
- The preclinical data support the advancement of BRD-810 to clinical trials for cancer treatment.
