The PROTAC selectively degrading BCL-Xinhibits the growth of tumors and significantly synergizes with Paclitaxel.

in Biochemical pharmacology by Fenglan Qiu, Yachuan Tao, Yue Chen, Zhuqin Shen, Xuan Huang, Wenfu Tan, Taomin Huang, Xin Cao

TLDR

  • SIAIS361034, a new PROTAC, selectively degrades BCL-X and shows promising results as a monotherapy or in combination with Paclitaxel for treating hematologic malignancies and small cell lung cancer.

Abstract

B-cell lymphoma extra large (BCL-X) 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-Xinhibitor 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-Xto 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-Xin tumor cells via a CRBN- and proteasome-dependent manner, with the half-maximal degradation concentration (DC) of below 10 nM. Moreover, SIAIS361034 effectively killed BCL-X-dependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro, with the half-maximal effective concentration (EC) 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-Xand 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.

Overview

  • The study focuses on the inhibitory effect of SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specific to BCL-X, on tumor growth, particularly on hematologic malignancies and small cell lung cancer (SCLC).
  • The study aims to elucidate the inhibitory effect of SIAIS361034 on tumors independently of the Hedgehog (Hh) pathway.
  • The primary objective is to evaluate the efficacy and safety of SIAIS361034 as a monotherapy or in combination with Paclitaxel (PTX) for the treatment of hematologic malignancies and SCLC.

Comparative Analysis & Findings

  • SIAIS361034 selectively and efficiently degraded BCL-X in tumor cells via a CRBN- and proteasome-dependent manner.
  • SIAIS361034 effectively killed BCL-X-dependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro and triggered apoptosis.
  • SIAIS361034 shows great potentiality in killing tumors cells, both as a monotherapy and in combination with PTX, with no exacerbating PTX-induced neutropenia.

Implications and Future Directions

  • SIAIS361034 represents a novel therapeutic strategy for the treatment of hematologic malignancies and SCLC, particularly in combination with PTX.
  • Further studies are needed to evaluate the long-term safety and efficacy of SIAIS361034, as well as its potential for combination with other chemotherapeutic agents.
  • Investigating the activity of SIAIS361034 in other types of cancer and exploring its potential as a single agent or in combination with immunotherapy may provide additional insights into its clinical utility.
Read Full Article