Advancements in Bcl-2 Inhibition: HZ-L105's Potency and Efficacy in Combating Drug Resistance in Hematological Malignancies

The article discusses the role of Bcl-2 as a critical regulator in preventing cell death, and its overexpression in various blood-related cancers. It highlights the FDA's approval of the first Bcl-2 inhibitor, Venetoclax, for certain types of leukemia and lymphoma. However, patients treated with Venetoclax over time have been observed to develop resistance due to specific mutations in the Bcl-2 protein.

The study introduces a new Bcl-2 inhibitor, HZ-L105, which is effective against both the wild-type Bcl-2 and the mutated forms, including Gly101Val and Asp103Tyr. The methods used to evaluate HZ-L105 included biochemical assays, cellular proliferation tests, human platelet viability measurements, cytochrome P450 inhibition assays, in vivo pharmacodynamic studies in mice, and preclinical pharmacokinetics in both mice and dogs.

The results showed that HZ-L105 was significantly more potent than Venetoclax in inhibiting Bcl-2 and its mutated forms. It also demonstrated a high level of selectivity for Bcl-2 over Bcl-xL, which is important for avoiding side effects such as thrombocytopenia. In cellular assays, HZ-L105 was more effective at suppressing cell growth in both the wild-type and mutated cell lines compared to Venetoclax.

Preclinical pharmacodynamic studies revealed that HZ-L105 had a rapid and potent antitumor effect in a mouse model of acute lymphoblastic leukemia. It also showed superior efficacy to Venetoclax at a lower dose. The pharmacokinetic studies indicated that HZ-L105 had favorable properties, including a long half-life and high area under the curve, which are desirable for drug efficacy.

Furthermore, HZ-L105 displayed a low potential for causing QT prolongation, a serious side effect associated with some drugs, and it had minimal interaction with other drugs due to its lack of inhibitory effect on cytochrome P450 enzymes. In a toxicity study, no deaths were observed at high doses, with leukopenia being the only side effect noted, similar to Venetoclax.

In conclusion, HZ-L105 has demonstrated promising results as a next-generation Bcl-2 inhibitor, with high potency, good oral bioavailability, strong anti-tumor activity, and favorable safety profiles. It could potentially offer new treatment options for patients with Bcl-2-dependent and Venetoclax-resistant hematological cancers.