Targeted protein degradation (TPD) molecules, including IMiD-based molecular glues and heterobifunctional degraders have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. To increase the efficacy vs. tolerability window of protein degradation and improve drug delivery we combine the catalytic approach of targeted protein degradation with the precision of tumor targeting therapeutic antibodies. Here, we describe the development of ORM-5029, a highly potent and selective GSPT1 degrader targeting HER2-expressing tumor cells. We first screened a panel of cell lines to identify tumors where treatment with a selective, membrane-permeable, molecular glue (SMol007) would exhibit the most potent GSPT1 degradation, integrated stress response, and ultimately apoptosis. HER2+ breast cancer cell lines were more sensitive to GSPT1 degradation than the average IC50 for all cell lines tested. Several of our GSPT1 degrader molecules were tested in HER2-positive tumor models and displayed a consistent pattern of potent cytotoxicity. An unbiased global proteomics evaluation of changes in abundance identified SMol006 as a specific GSPT1 degrader, with no significant depletion of over 6500 other proteins detected. To evaluate whether antibody delivery could provide a potency increase of Smol006 and other GSTP1 degrader payloads, we conjugated these payloads to the HER2-targeting antibodies, trastuzumab and pertuzumab. Given the comparable activity of both antibodies and frequent use of trastuzumab as the antibody domain of several ADCs, we selected pertuzumab as our targeting antibody. Further medicinal chemistry optimization and evaluation of many linker-payloads led to the identification of our first preclinical AnDC candidate ORM-5029, which is composed of SMol006, a highly-potent GSPT1 degrader conjugated to pertuzumab via a clinically-validated Val-Cit PABc linker. ORM-5029 treatment in the HER2-expressing cell lines showed 10-1000 fold superiority in potency compared to SMol006, Kadcyla and/or Enhertu treatment. We evaluated ORM-5029 in several in vivo xenograft models and observed robust efficacy, following a single-dose treatment testing as low as 3 mg/kg. In the BT474 xenograft model, treatment with ORM-5029 demonstrated single-dose activity superior to Kadcyla, and comparable to Enhertu when given at an equivalent dose. In an HCC1569 xenograft model, tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in expression of previously described integrated stress response biomarker genes. ORM-5029 is currently in preclinical development as a potential first-in-class targeted protein degrader therapy with HER2-targeted delivery. Citation Format: James Palacino, Chen Bai, Yong Yi, Anna Skaletskaya, Khuloud Takrouri, Wesley Wong, Min-Soo Kim, Dong-Ki Choi, Da-Young Kim, Yeonhee Yang, Jiae Kook, Pedro Lee, Hangyeol Jeong, Sang-Mi Jee, Jiyun Park, Ki-Hwan Chang, Nathan Fishkin, Peter U. Park. ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3933.
This study evaluated the potential use of senescence-inducing small molecules in the treatment of melanoma. We screened commercially available small-molecule libraries with high-throughput screening and high-content screening image-based technology. Our findings showed an initial hit with the embedded N-arylpiperidine-3-carboxamide scaffold-induced senescence-like phenotypic changes in human melanoma A375 cells without serious cytotoxicity against normal cells. A focused library containing diversely modified analogues were constructed and examined to evaluate the structure–activity relationship of N-arylpiperidine-3-carboxamide derivatives starting from hit 1. This work identified a novel compound with remarkable antiproliferative activity in vitro and demonstrated the key structural moieties within.
Targeted protein degraders (TPDs) have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. Prior reports of small-molecule GSPT1 degraders such as CC-90009 in AML demonstrate potent anti-tumor cytotoxicity, but with a potentially narrow therapeutic index. To increase the efficacy vs. tolerability window of TPDs and improve drug delivery, we introduce TPD-Squared (TPD2 TM), a dual-targeted protein degradation approach of combining the catalytic mechanism of targeted protein degradation with the precision of tumor-targeting therapeutic antibodies. We have previously shown in vitro and in vivo efficacy with a HER2-targeted TPD2 conjugate: ORM-5029. Following on that success, we generated conjugates using a CD33-targeting antibody (OR000283) produced by engineering the FAb (H&L) sequences from gemtuzumab onto an IgG1 Fc with N297A variant to inhibit Fc-γR binding. Medicinal chemistry optimization of linker-payloads led to the identification of ORM-6151, which is composed of SMol006, a highly potent GSPT1 degrader conjugated to OR000283 via a novel β-glucuronide releasable linker. ORM-6151 treatment in CD33-expressing cell lines showed picomolar activity with 10-1000-fold greater potency compared to several GSPT1 degrader molecules, including CC-90009 or Mylotarg, and had robust activity in Mylotarg-resistant lines (AML193 and Kasumi6). ORM-6151 also exhibited picomolar potency in in vitro cytotoxicity to primary relapsed/refractory AML patient blasts, with better potency than CC-90009 and Mylotarg. We evaluated ORM-6151 in several in vivo disseminated xenograft models and observed robust efficacy following a single treatment at doses as low as 0.1 mg/kg. Tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in the expression of previously described integrated stress response biomarker genes. In summary, ORM-6151 is a promising, potential therapy for AML and currently in preclinical development as a first-in-class targeted protein degrader therapy with CD33-targeted delivery. Citation Format: James Palacino, Pedro Lee, Hangyeol Jeong, Yeonjoon Kim, Yoojin Song, Uttapol Permpoon, Wesley Wong, Chen Bai, Nathan Fishkin, Khuloud Takouri, Eunjun Yu, Yong Yi, Anna Skaletskaya, Min-Soo Kim, Da-Yeong Kim, Dong-Ki Choi, Peter U. Park. ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2700.
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