The PROTAC selectively degrading BCL-XL inhibits the growth of tumors and significantly synergizes with Paclitaxel

Fenglan Qiu; Yachuan Tao; Yue Chen; Zhuqin Shen; Xuan Huang; Wenfu Tan; Taomin Huang; Xin Cao

doi:10.1016/j.bcp.2024.116731

The PROTAC selectively degrading BCL-X_L inhibits the growth of tumors and significantly synergizes with Paclitaxel

Biochem Pharmacol. 2024 Dec 19:116731. doi: 10.1016/j.bcp.2024.116731. Online ahead of print.

Authors

Fenglan Qiu¹, Yachuan Tao¹, Yue Chen¹, Zhuqin Shen², Xuan Huang³, Wenfu Tan⁴, Taomin Huang⁵, Xin Cao⁶

Affiliations

¹ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
² Department of Pharmacy, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China.
³ Zhongshan Hospital Institute of Clinical Science, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁴ Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: wftan@fudan.edu.cn.
⁵ Department of Pharmacy, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China. Electronic address: taominhuang@126.com.
⁶ Zhongshan Hospital Institute of Clinical Science, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: caox@fudan.edu.cn.

PMID: 39709037
DOI: 10.1016/j.bcp.2024.116731

Abstract

B-cell lymphoma extra large (BCL-X_L) is an important anti-apoptotic protein of BCL-2 family. It is frequently overexpressed in various hematologic and solid tumors, often positively correlated with chemotherapy resistance in tumors. However, the clinical development of the small molecule BCL-X_L inhibitor ABT-263 has been challenged on account of its on-target and dose-limiting toxicity. We have previously reported that SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specifically targeting BCL-X_L to cereblon (CRBN) E3 ligase for degradation, represents a novel Hedgehog (Hh) inhibitor and inhibits tumors addiction to the Hh pathway activity with little influence on platelets. However, the inhibitory effect of SIAIS361034 on tumors independent on Hh pathway remains to be fully elucidated. In the present study, we explored its inhibitory effect on the growth of hematologic malignancies and small cell lung cancer (SCLC). Our results showed that SIAIS361034 selectively and efficiently degraded BCL-X_L in tumor cells via a CRBN- and proteasome-dependent manner, with the half-maximal degradation concentration (DC₅₀) of below 10 nM. Moreover, SIAIS361034 effectively killed BCL-X_L-dependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro, with the half-maximal effective concentration (EC₅₀) of 16.09 nM, and triggered apoptosis of MOLT-4 cells. SIAIS361034 obviously inhibited the growth of MOLT-4 xenografts with tumor growth inhibition rate (TGI) of 96.1 %, and did not induce acute and severe thrombocytopenia at therapeutic dosages. Furthermore, SIAIS361034 potently boosted the response of SCLC cells to Paclitaxel (PTX) and yielded more apoptosis in vitro by concurrently reduced the expression of BCL-X_L and myeloid cell leukemia 1 (MCL-1), respectively. Meanwhile, we observed that SIAIS361034 significantly synergized with PTX to inhibit the growth of SCLC xenografts in vivo, without causing exacerbating PTX-induced neutropenia. Taken together, SIAIS361034, shows great potentiality in killing tumors cells, both as a monotherapy and in combination with PTX.

Keywords: Acute lymphoblastic leukemia; BCL-X(L); MCL-1; PROTAC; Small cell lung cancer.