DIACC3010
An optimized S6K inhibitor to overcome limitations of first and new PAM inhibitors
In just over 20 years, protein kinase inhibitors have changed the face of oncology and opened the new eras of targeted therapies and precision medicine. However, with few exceptions, no patient can be cured by one of these drugs alone. Today, scientists seek to develop novel kinase inhibitors[1] with improved selectivity and the potential to overcome resistances. The oral S6K optimized inhibitor DIACC3010 displays these two characteristics and reaches-up brain metastases. After having successfully completed a phase I trial in patients with advanced/refractory solid tumors, including breast cancer, the drug candidate will soon be evaluated in an exploratory phase II program in solid tumors.
The last node of the most important cell signaling routes
The ribosomal protein S6 kinase (also known as S6K) is a serine-threonine protein kinase involved in almost every aspect of tumor cell biology[2]: survival, growth, invasion, metastasis, immune tolerance, drug resistance… Thus, in many cancers (renal cell carcinoma, non-small-cell lung cancer, breast tumors…), the aberrant regulation of S6K is associated with disease aggressiveness and poor patient outcome.
The multifaceted role of S6K in cancer progression
*The EMT, is the physiological process in which epithelial cells gradually acquire the migratory and invasive properties of mesenchymal cells, a critical event in tumor metastasis; **Tumor microenvironment; ***Cancer-Associated Fibroblasts.
In terms of topology, S6K is a downstream node of the PAM[3] signaling cascade, one of the most frequently overactivated pathways in cancer cells[4]. It also interacts with several metabolic nodes, notably the nuclear estrogen receptor (ER), the established driver of 80% of breast cancers[5].
The S6K-AKT1/3 signaling pathway
The pathway is activated in response to an extracellular signal (growth factor, hormone...…) captured by a receptor of the tyrosine kinase family. Once activated, it triggers a cascade of molecular handshakes from the surface to the cell nucleus where genes will ensure a cellular response in accordance with the signal received (growth, survival...).
PAM inhibitors block tumor progression, but their scope is still limited
To date, the only approved indirect “S6K inhibitors” in oncology target upstream nodes of the pathway: PI3K inhibitors[6] (copanlisib, duvelisib, alpelisib) and the mTOR inhibitors[7] rapamycin (sirolimus) and its analogues (everolimus, and temsirolimus). Overall, these drugs have limited efficacy (notably because they induce multiple feedback loops and compensatory pathways), significant toxicity and their long-term use leads to drug resistance. Still in development, new PAM inhibitors target other isoforms and nodes of the pathway (alone or simultaneously). More selective and less toxic[8], they could overcome resistance to certain cancer drugs[9][10] and act in synergy with them.
Poster presented at AACR2023
The unique features of DIACC3010
The mechanism of action of the drug candidate gives it a series of advantages over first and new PAM inhibitors, both in terms of efficacy and safety:
- DIACC3010 interrupts the PAM traffic by inhibiting S6K but it also blocks two of the three AKT isoforms (AKT1 and AKT3), which suppresses any excess activated AKT that result from a negative feedback loop (the Achilles heel of most PAM inhibitors).
- DIACC3010 spares AKT2 to prevent hyperglycemia, a major adverse effect in patients treated with PAM inhibitors and most likely resulting from AKT2 inhibition.
- DIACC3010 is designed to cross the blood-brain barrier, a rare property among cancer drugs, as illustrated by the very low survival rate of patients with brain metastases[11][12].
- DIACC3010 controls the hormone-independent activation of estrogen receptor (ER)[13][14] a key feature to overcome endocrine therapy resistance in breast cancer patients.
Clinical Development
Solid preclinical studies with this compound strongly supported the clinical development of DIACC3010, for which a phase 1 trial has been completed in 101 patients with advanced cancer resistant to multiple standard therapies, including metastatic ER+ HER2- breast cancer patient population with and without ESR1 mutations[15]. DIACC3010 was well tolerated in monotherapy and potential biomarkers of pharmacological activity were seen in peripheral blood mononuclear cells and tumor tissues. Combined with trastuzumab or tamoxifen, DIACC3010 also demonstrated early signals of antitumor activity in breast cancer patients.
The drug candidate will soon be evaluated in an exploratory phase II program in 2 incurable solid tumors: endocrine resistant ER+ HER2- breast cancers (30-50 % of patients), including those with ESR1 mutations, and glioblastoma (the most common and aggressive brain tumor).