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LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

ABSTRACT: Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.

SUBMITTER: Qiu J

PROVIDER: S-EPMC9037595 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

Qiu Jiahao J Bai Xinfa X Zhang Wenjing W Ma Mingxu M Wang Wenyan W Liang Ye Y Wang Hongbo H Tian Jingwei J Yu Pengfei P

Frontiers in pharmacology 20220411

Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthe ...[more]

PMID: 35479314

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Project description:BackgroundRanpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).MethodsThe DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.Results(Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50???1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose.ConclusionsA new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

Project description:IntroductionTriple negative breast cancer (TNBC) is the most aggressive and hard-to-treat subtype of breast cancer, affecting 10-20% of all women diagnosed with breast cancer. Surgery, chemotherapy and hormone/Her2 targeted therapies are the cornerstones of treatment for breast cancer, but women with TNBC do not benefit from these treatments. Although the prognosis is dismal, immunotherapies hold significant promise in TNBC, even in wide spread disease because TNBC is infiltrated with more immune cells. This preclinical study is proposing to optimize an oncolytic virus-infected cell vaccine (ICV) based on a prime-boost vaccination strategy to address this unmet clinical need.MethodsWe used various classes of immunomodulators to improve the immunogenicity of whole tumor cells in the prime vaccine, followed by their infection with oncolytic Vesicular Stomatitis Virus (VSVd51) to deliver the boost vaccine. For in vivo studies, we compared the efficacy of a homologous prime-boost vaccination regimen to a heterologous strategy by treating 4T1 tumor bearing BALB/c mice and further by conducting re-challenge studies to evaluate immune memory responses in surviving mice. Due to the aggressive nature of 4T1 tumor spread (akin to stage IV TNBC in human patients), we also compared early surgical resection of primary tumors versus later surgical resection combined with vaccination.ResultsIn vitro results demonstrated that immunogenic cell death (ICD) markers and pro-inflammatory cytokines were released at the highest levels following treatment of mouse 4T1 TNBC cells with oxaliplatin chemotherapy and influenza vaccine. These ICD inducers also contributed towards higher dendritic cell recruitment and activation. With the top ICD inducers at hand, we observed that treatment of TNBC-bearing mice with the influenza virus-modified prime vaccine followed by VSVd51 infected boost vaccine resulted in the best survival. Furthermore, higher frequencies of both effector and central memory T cells along with a complete absence of recurrent tumors were observed in re-challenged mice. Importantly, early surgical resection combined with prime-boost vaccination led to improved overall survival in mice.ConclusionTaken together, this novel cancer vaccination strategy following early surgical resection could be a promising therapeutic avenue for TNBC patients.

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LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

Publications

LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer.

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