Abstract
Targeted Protein Degradation (TPD) is a novel therapeutic modality that uses heterobifunctional small molecules to redirect the cellular machinery responsible for protein degradation and cellular homeostasis, the ubiquitin-proteasome system (UPS), toward specific disease-causing proteins through spatial proximity with the use of affinity rather than occupancy-based catalysis, delivering a potentially transformative new way to treat disease. To realize on the promise of this disease-agnostic technology, we have taken a unique approach to target selection, where we focus on targets that are either undrugged or inadequately drugged within key signaling pathways with clear clinical validation and validation through human genetics/causal biology, and where TPD is the best or the only solution - defining a clear path to early differentiation from existing technologies and agents. Additionally, our comprehensive drug discovery engine utilizes computational tools, fit-for-purpose technologies, and quantitative translational models to design potent and selective degraders and drive consistent fidelity of translation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and early efficacy from preclinical models to patients, as observed across all our clinical programs. Within oncology, TPD has the potential to redefine treatment paradigms given the existence of numerous clinically validated targets coupled with the limitations of existing cancer therapies in key areas such as druggability, selectivity, resistance, potency, and durability. Here, we share vignettes that highlight the advantage of TPD over other technologies and strong preclinical to clinical translation from our first-in-class oncology programs.
KT-333 is a potent, highly selective, heterobifunctional small molecule protein degrader of signal transducer and activator of transcription 3 (STAT3), a traditionally undrugged transcription factor recognized as a key component of the Janus Kinase (JAK)-STAT signaling pathway with both tumor cell intrinsic and tumor cell extrinsic effects on the tumor microenvironment. Although multiple drugs have been approved that target upstream effectors signaling through STAT3, no known drugs selectively block STAT3 broadly across all relevant cell types or address both phosphorylation-dependent and -independent functions of STAT3. For these reasons, we believe that STAT3 degraders may provide a solution to the development of targeted and selective drugs to address multiple STAT3 dependent pathologies. In preclinical studies, KT-333 has shown durable single agent antitumor activity across multiple liquid and solid tumor models. Additionally, degradation of STAT3 has both antiproliferative and proapoptotic effects on tumor cells as well as immunomodulatory effects on tumor cells and the tumor microenvironment. This leads to robust anti-tumor activity in preclinical models of STAT3-dependent T-cell lymphomas and syngeneic models of solid tumors combined with immunotherapies such as checkpoint blockade - which only work in a small percentage of patients.
Interim data from the Phase 1a clinical trial demonstrated early signs of antitumor activity at doses that were generally well-tolerated and associated with substantial STAT3 knockdown in blood and tumor. Preclinical to clinical translation showed strong responses in both cutaneous T-cell lymphoma (CTCL) and in Hodgkin's lymphoma as well as induction of an Interferon (IFN)-ƴ response in tumor and blood that preclinically was shown to enhance the response of solid tumors to anti-PD-1 drugs. We believe this supports KT-333’s potential to address both hematological malignancies as a single agent and solid tumors as a potential novel combination therapy with anti-PD-1 or other targeted therapies.
KT-253 is a highly potent heterobifunctional degrader of the murine double minute 2 (MDM2) oncoprotein, a key E3 ligase that modulates the most common tumor suppressor, p53. p53 is a transcription factor that regulates cellular responses to stress and guides cell fate decisions such as cell cycle arrest, DNA repair, senescence, and apoptosis. Loss of p53 function leads to inability of cells to respond to cellular stressors such as DNA damage and leads to genetic instability, a hallmark of cancer. Notably, p53 remains intact in close to 50% of cancers. While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been found to induce a feedback loop that increases MDM2 protein levels, which can repress p53 and therefore limit their efficacy. In preclinical studies, KT-253, unlike small molecule inhibitors of MDM2, has shown the ability to overcome the MDM2 feedback loop and thereby robustly activate the p53 pathway, even with brief exposures. KT-253 more effectively upregulates and activates p53 in tumors in vivo compared to small molecule MDM2 inhibitors, and this translates into antitumor responses in p53 wild-type acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and Merkel cell carcinoma (MCC) models with just single doses of KT-253. These results support an intermittent dosing strategy for KT-253 that enables maximum p53 pathway activation for a limited period of time in tumor cells leading to rapid apoptosis while mitigating the impact of target engagement in normal cells in order to improve the therapeutic index relative to MDM2 small molecule inhibitors.
Interim data from the Phase 1a clinical trial show evidence of target engagement and p53 pathway activation, along with initial signs of antitumor activity without dose limiting toxicities (DLTs), including typical hematological toxicity, and are supportive of our therapeutic hypothesis for MDM2 degraders and the potential to improve the therapeutic index compared to MDM2 small molecule inhibitors. We demonstrated proof of mechanism in the first 2 dose levels (DLs) with exposure-dependent upregulation of plasma GDF-15 levels. GDF-15 is a transcriptional target of p53, and as such it serves as a downstream biomarker of p53 upregulation following MDM2 degradation. This was consistent with the pattern of p53 activation in preclinical models associated with KT-253 antitumor activity. One patient with a partial response had MCC metastatic to abdominal lymph nodes and skin who had previously been treated with chemotherapy as well as multiple different immune checkpoint inhibitors. Lymph node metastases were responding after the first 2 cycles of treatment, as was the skin metastasis, and after 4 cycles there was an approximately 60% reduction in nodal tumor burden and resolution of the skin metastasis.
In summary, these preclinical and early clinical findings support a clear degrader advantage by eliminating oncogenic proteins in key signaling pathways and validate our differentiated target selection and translational strategies to advance a new generation of medicines.
Citation Format: Nello Mainolfi. Targeting validated but un-drugged oncogenes with small molecule protein degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY12-01.
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Just Published
May 1, 2024
Jing Wang + 20
Open Access