Abstract 2133: In pursuit of MCL-1 inhibitors with improved therapeutic window for the treatment of hematological malignancies: Discovery of JNJ-4355

Rombouts, Frederik; William, Lento; Velter, Ingrid; Vos, Ann; Peschiulli, Aldo; Tristan, Reuillon; Blanco, Maria Dominguez; Jouffroy, Matthieu; McQueen, Lisa; Steyvers, Helena; Bekkers, Mariette; Altrocchi, Cristina; Pietrak, Beth; Koo, Seong Joo; Szewczuk, Lawrence M.; Walker, David G.; Packman, Kathryn; Bueters, Ruud; Vinken, Petra; Johnson, Amy J.; Attar, Ricardo M.; Philippar, Ulrike

doi:10.1158/1538-7445.am2022-2133

Cited by 5 publications

(15 citation statements)

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“…47 It is hence important not to interpret the observed acute CTCM hazard scores in the context of Mcl-1 acute on-target cardiotoxicity, which is more optimally studied in vivo as we reported earlier. 49 Here, the risk of ontarget cardiotoxicity was minimized by optimizing the pharmacokinetic (PK) profile of the allyl-THF inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“… a CYP450 cocktail consisting of isoforms 1A2, 2C19, 2C8, 2C9, 2D6, and 3A4. b See ref . c Low A → B and B → A compound recovery was observed (<40%). …”

Section: Resultsmentioning

confidence: 99%

“… a See the Experimental Section for assay protocols. b Binding activity assessed by an HTRF binding assay utilizing the Bim BH3 peptide as the binding partner for terbium-labeled Mcl-1. c MOLP-8 multiple myeloma cancer cell killing potency assessed by the Caspase-Glo 3/7 assay. d Emphasized in bold are experimental log P values, the molecules being neutral at this pH. e In vitro clearance determined in human or mouse liver microsomes (per mg of protein). f See ref . g Thermodynamic (equilibrium) solubility. …”

Section: Resultsmentioning

confidence: 99%

“…This work culminated with the discovery of JNJ-78394355 (9)�an efficacious IV-administered Mcl-1 inhibitor. 49 Second, we extensively profiled our lead compounds in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) to evade significant off-target activity on cardiac ion channels exacerbating the potential on-target cardiotoxicity with Mcl-1 inhibition.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This would trigger apoptosis in primed tumor cells while potentially avoiding mitochondrial toxicity in cardiomyocytes which, according to the literature, requires more prolonged Mcl-1 coverage. This work culminated with the discovery of JNJ-78394355 ( 9 )an efficacious IV-administered Mcl-1 inhibitor …”

Section: Introductionmentioning

confidence: 99%

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Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

et al. 2023

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Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.

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Section: Resultsmentioning

confidence: 99%

“… a CYP450 cocktail consisting of isoforms 1A2, 2C19, 2C8, 2C9, 2D6, and 3A4. b See ref . c Low A → B and B → A compound recovery was observed (<40%). …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

et al. 2023

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Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

Deng,

Han,

Liu

et al. 2024

J. Med. Chem.

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As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein− protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment. This Perspective aims to discuss the mechanism by which Mcl-1 regulates apoptosis and non-apoptotic functions in cancer cells and to outline the discovery and optimization process of potent Mcl-1 modulators. In addition, we summarize the structural characteristics of potent inhibitors that bind to Mcl-1 through multiple co-crystal structures and analyze the cardiotoxicity caused by current Mcl-1 inhibitors, providing prospects for rational targeting of Mcl-1. ■ SIGNIFICANCE • Pharmacological inhibition of protein−protein interactions between Mcl-1 and its substrates has become a promising approach to induce apoptotic or nonapoptotic functions in the treatment of various diseases. • Recent advancements in targeting Mcl-1 for tumor therapy are systematically summarized from medicinal chemistry insights. • The structural characteristics of potent inhibitors binding with Mcl-1 are analyzed. • The cardiotoxicity of Mcl-1 inhibitors is discussed, and structural modification strategies for future Mcl-1 inhibitors development are proposed.

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Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

Hekking,

Maroto,

van Kekem

et al. 2024

J. Med. Chem.

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Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein−protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

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Abstract 2133: In pursuit of MCL-1 inhibitors with improved therapeutic window for the treatment of hematological malignancies: Discovery of JNJ-4355

Cited by 5 publications

References 0 publications

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

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