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APG-2575 is a new type of oral Bcl-2 small molecule inhibitor, which restores the apoptosis mechanism of tumor cells by selectively inhibiting Bcl-2 protein, thereby killing tumors
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In pre-clinical studies, APG-2575 is used alone or in combination with the company's own MDM2-p53 inhibitor, BTK inhibitor, CD20 mAb and PI3K inhibitor, and has good anti-tumor activity against a variety of B cell malignancies
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APG-1252 can target Bcl-2 and Bcl-xL to repair cell apoptosis
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In fact, the apoptosis escape of tumor cells is not based on a single target and a single mechanism, so the inhibition of multiple targets can further enhance the anti-tumor effect
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However, multi-target inhibition of severe platelet toxicity is a common clinical adverse event.
In the early stage, AbbVie's ABT-263 was terminated due to severe platelet toxicity
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In this regard, APG-1252 improves its therapeutic index through prodrug design and reduces platelet toxicity
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(2) FCN-338 is a selective inhibitor of Bcl-2, currently in phase I clinical research
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Pre-clinical studies have confirmed that FCN-338 is an oral and highly effective selective inhibitor of BCL-2, which has the effect of treating hematological malignancies
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In October 2020, Fotron Pharmaceuticals and Eli Lilly Pharmaceuticals signed a "Licensing Agreement", granting Eli Lilly Pharmaceuticals FCN-338 exclusive rights in other regions of the world except Mainland China, Hong Kong and Macau
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(3) BeiGene's BGB-11417 is a Bcl-2 inhibitor.
It will start a phase I clinical trial in Q1 of 2021, and is indicated for B-cell malignant tumors
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In vitro experiments show that the inhibitory effect of BGB-11471 on BCL-2 is ten times that of Venetoclax, and the inhibitory effect of BCL2-G101V mutant protein is more than 50 times that of Venetoclax
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On EHA 2021, BeiGene announced the Phase I early data of BGB-11417, and the results showed that BGB-11417 is tolerable in patients with R/R NHL at dose-escalation levels
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(4) Guangzhou Lupeng Pharmaceutical's LP-108 is a Bcl-2 inhibitor, and it was approved for clinical use in August 2020.
The indication is combined chemotherapy for the treatment of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) Or acute myeloid leukemia (AML)
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On July 28, 2021, Lupeng Pharmaceuticals completed a US$35 million Pre-B round of financing.
This round of financing was led by Temasek, Qingchi Capital, Eli Lilly Asia Fund (LAV), Fengchuan Capital and other strategic investors.
Cast
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summary

The Bcl-2 protein has gone through ups and downs from the proof-of-concept of the drug target to the listing of Venetoclax
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Successively encountered problems such as the identification of small molecule lead compounds, druggability, and target selectivity.
After the failure of ABT-737 and ABT-263, the basic research of Bcl-2 protein was finally transformed into an effective target for clinical treatment
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Drug research and development is by no means easy.
Risks and opportunities coexist.
I sincerely hope that domestic companies that deploy Bcl-2 inhibitors can continue their efforts, make every success, and make further progress
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