PDB 8el0 citation summary ‹ Protein Data Bank in Europe (PDBe)

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

Yuda J, Will C, Phillips DC, Abraham L, Alvey C, Avigdor A, Buck W, Besenhofer L, Boghaert E, Cheng D, Cojocari D, Doyle K, Hansen TM, Huang K, Johnson EF, Judd AS, Judge RA, Kalvass JC, Kunzer A, Lam LT, Li R, Martin RL, Mastracchio A, Mitten M, Petrich A, Wang J, Ward JE, Zhang H, Wang X, Wolff JE, Bell-McGuinn KM, Souers AJ

Commun Med (Lond) 3 154 (2023)

Related entries: 8ekx, 8el1

Cited: 1 times

PMID: 37880389

10.1038/s43856-023-00380-z

Abstract

Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.

Background

MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).

Methods

Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy.

Results

Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings.

Conclusion

The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Articles - 8el0 mentioned but not cited (1)

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients. Yuda J, Will C, Phillips DC, Abraham L, Alvey C, Avigdor A, Buck W, Besenhofer L, Boghaert E, Cheng D, Cojocari D, Doyle K, Hansen TM, Huang K, Johnson EF, Judd AS, Judge RA, Kalvass JC, Kunzer A, Lam LT, Li R, Martin RL, Mastracchio A, Mitten M, Petrich A, Wang J, Ward JE, Zhang H, Wang X, Wolff JE, Bell-McGuinn KM, Souers AJ. Commun Med (Lond) 3 154 (2023)

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