In human cancer, the finding of suppression of p53 by overexpression of MDM2, whether by gene amplification or protein upregulation, inspired the development of small-molecule MDM2 inhibitors to restore the p53 tumor-suppressor pathway ( 11). Importantly, both MDM2 and MDMX are essential to negative regulation and homeostasis of p53 at the organism level, as evidenced by the embryonic lethality of MDM2 or MDMX deletion in mice ( 9, 10). Although MDMX does not possess E3 ligase activity, it enhances MDM2-mediated degradation of p53 ( 8). Whereas the MDM2–p53 interaction results in p53 ubiquitination and degradation, an analogous helix-in-groove interaction between MDMX and p53 thwarts transcriptional activity by complex formation. MDM2 is an E3 ubiquitin-protein ligase that engages the transactivation domain of p53 by a helix-in-groove interaction ( 7). Conversely, many human cancers retain wild-type TP53, making reactivation of the natural p53 pathway by targeted inhibition of MDM2 and MDMX in TP53 wild-type cancer cells an appealing strategy for therapeutic intervention. Mutation of the TP53 gene that encodes the p53 tumor-suppressor protein has been observed in approximately 50% of adult and 4% of childhood cancers, highlighting the importance of p53 signaling ( 6). The latter two mechanisms are mediated by protein–protein interactions between p53 and its negative regulators mouse double minute 2 (MDM2), which binds and destroys p53, and MDMX, which binds and sequesters p53 ( 4, 5). To subvert this antitumor functionality, cancer cells neutralize p53 by deletion, mutation, degradation, or sequestration ( 2, 3). The natural tumor-suppressor function of p53 involves responding to DNA damage by arresting cell division, allowing for repair, and if repair is unsuccessful, inducing an apoptotic response. IntroductionĬommonly referred to as “the guardian of the genome,” p53 plays a central role in the mechanisms that defend the human body from cancer ( 1). Strikingly, the hematopoietic toxicity typically observed for selective MDM2 inhibitors was nearly absent for ALRN-6924, suggesting that dual MDM2/MDMX inhibition may allow for more complete p53 activation with a toxicity profile that would allow for combination therapy and use as a chemoprotection agent. We evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor effects of ALRN-6924 in patients with solid tumors or lymphomas, and show that ALRN-6924 was well tolerated with encouraging antitumor activity, including durable complete and partial responses with more than half of evaluable patients achieving disease control. ALRN-6924, a dual MDM2/MDMX inhibitor, is the first member of this new modality to reach the clinic. Stapled peptides are a new therapeutic modality capable of disrupting protein–protein interactions in cells. However, no inhibitors of MDMX, the second regulator of p53, have been tested clinically, due in part to the challenge of developing small-molecule inhibitors of the p53–MDMX interface. The p53 tumor-suppressor protein and its endogenous regulator mouse double minute 2 (MDM2) have been a focus of cancer research for over 30 years, with several small-molecule inhibitors of MDM2 evaluated in clinical trials. The recommended phase 2 dose was schedule A, 3.1 mg/kg.
Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease.
In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Seven patients had infusion-related reactions 3 discontinued treatment. No G3/G4 thrombocytopenia was observed in any patient. At the MTD in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. Seventy-one patients were enrolled: 41 in arm A (0.16–4.4 mg/kg) and 30 in arm B (0.32–2.7 mg/kg).
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