Lonitoclax

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Lonitoclax

CAS 2952589-57-8

MF C43H45ClN4O5 MW733.3 g/mol

5-[5-chloro-2-[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethylpyrrole-3-carboxamide

5-(5-chloro-2-{(3S)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1H)-carbonyl}phenyl)-N-(4-
hydroxyphenyl)-N-[(3-methoxy-2-methylphenyl)methyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ZE50-0134, ZE50 0134, Lomond Therapeutics, CANCER, 76NBC3X6A3

Lonitoclax (also known as ZE50-0134) is an investigational, next-generation, orally administered B-cell lymphoma 2 (Bcl-2) inhibitor being developed for the treatment of hematologic malignancies like Acute Myeloid Leukemia (AML) and Chronic Lymphocytic Leukemia (CLL). Developed by Lomond Therapeutics, the drug is engineered as a highly selective option to improve upon existing first-generation Bcl-2 inhibitors like venetoclax.

Mechanism and Advantages Over Venetoclax

Unlike earlier therapies, lonitoclax features a unique binding mode and a structurally distinct chemotype. Its design yields several pharmacology advantages:

Higher Selectivity: It binds tightly to Bcl-2 while demonstrating exceptional selectivity over Bcl-xL, which helps lower hematologic toxicities.
Limited Immune Suppression: In preclinical data, lonitoclax spared healthy non-malignant immune cells (B cells, CD8 T cells, and NK cells), a major shift from the immunosuppressive profile of venetoclax.
Reduced Drug Interaction & Accumulation: It features a shorter half-life (~9–10 hours) and minimal CYP3A4 (P4503A4) inhibition. This prevents the drug from building up dangerously and mitigates the risk of Tumor Lysis Syndrome (TLS), potentially enabling safer outpatient treatments.

Clinical Development Status

Lonitoclax is currently advancing through early-phase clinical trials:

IND Clearances: The U.S. FDA cleared Investigational New Drug (IND) applications evaluating lonitoclax for CLL/SLL and as a combination treatment for relapsed or refractory AML.
Healthy Volunteer Studies: Phase 1 single ascending dose (SAD) studies in healthy adults confirmed that the drug is well tolerated with linear pharmacokinetics and no significant safety issues. Target engagement was confirmed through plasma apoptosis assays.
Combination Trials: Active Phase 1b multicenter trials are underway evaluating the safety, efficacy, and synergy of lonitoclax when combined with hypomethylating agents like azacitidine in AML patients.

SYN

US20250115577, Compound 7

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023129553&_cid=P11-MQVQMH-93381-1