Abstract 4482: S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models

Abstract

Mcl-1 is highly expressed in a variety of human cancers (including those of hematopoietic and lymphoid origin) and is exploited by cancer cells to evade cell death and to develop resistance to diverse chemotherapeutic agents. We disclose, for the first time, the structure of S64315 (also named MIK665) a highly potent and selective inhibitor of Mcl-1 with improved potency over its predecessor S63845 (Kotschy et al, Nature, 2016). S64315/MIK665 is currently in phase 1 in AML (Acute Myeloid Leukemia) and MDS (Myelodysplastic Syndrome) (EudraCT 2016-003768-38, NCT 02979366) and in MM (Multiple Myeloma) and lymphoma (NCT02992483). A fragment-based, structure-guided drug discovery effort led to the identification of S64315/MIK665 that binds to human Mcl-1 with a sub-nanomolar affinity (Ki 0.048 nM) and selectively over other anti-apoptotic Bcl-2 family members. It has similar affinity for human, rat, dog and monkey Mcl-1 but about a ten-fold lower affinity for mouse Mcl-1. S64315/MIK665 causes dose-dependent activation of the intrinsic apoptosis pathway in a Bax/Bak-dependent manner, as measured by increased caspase activity and cleaved PARP. S64315/MIK665 shows strong cell killing activity in a diverse panel of human hematological tumor cell lines, including AML, lymphoma and MM. The activity profile of S64315/MIK665 is distinct from that of venetoclax, a selective Bcl2 inhibitor. In vivo, S64315 as single agent demonstrated potent and dose-dependent apoptotic and antitumor response after intravenous administration in several human hematological tumor models grafted in immuno-compromised mice and rats. Complete regression of established tumors, at well tolerated doses, was achieved using different intravenous dosing regimens in rats as well as in mice. Finally, dual BH3-mimetic targeting approach combining S64315/MIK665 with BCL2 inhibitors showed strong and durable antitumor responses in several hematological tumor models both in vitro and in vivo. Citation Format: Ana Leticia Maragno, Prakash Mistry, András Kotschy, Zoltán Szlavik, James Murray, James Davidson, Gaëtane Le Toumelin-Braizat, Maïa Chanrion, Alain Bruno, Audrey Claperon, Heiko Maacke, Erick Morris, Youzhen Wang, Alix Derreal, Márton Csekei, Attila Paczal, Zoltán Szabo, Szabolcs Sipos, Agnes Proszenyak, Balázs Balint, Allan Surgenor, Pawel Dokurno, Natalia Matassova, Ijen Chen, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Fabienne Grave, Frédéric Colland, Ensar Halilovic, Olivier Geneste. S64315 (MIK665) is a potent and selective Mcl1 inhibitor with strong antitumor activity across a diverse range of hematologic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4482.

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

“…S64315 (MIK665), a highly selective MCL-1 inhibitor can act partly similar to AZD5991 by inhibiting MYC activity and inducing Bax/Bak-mediated apoptosis. S64315 is a well-tolerated compound capable of inducing dose-dependent apoptosis, demonstrating potent antitumor activity in hematological malignancies such as AML, multiple myeloma, and lymphoma [ 732 ]. Since BCL-2 family members and MYC act cooperatively in cancers [ 733 ], inhibiting MCL-1 could be a potential approach for MYC-involved cancers.…”

Fragment-Based Drug Discovery by NMR. Where Are the Successes and Where can It Be Improved?

“…The third case study presents an overview of the most crucial optimisation steps in the development of the molecule S64315, also known as MIK665 (Szlávik et al, 2019) (Figure 4A). S64315 is one of the most recent inhibitors currently being tested in clinical trials for targeting the BCL anti-apoptotic family, MCL-1 (Maragno et al, 2019). A series of studies indicated that MCL-1 is over-expressed in many cancer types (multiple myeloma, lymphomas, leukaemia) and therefore it is widely recognised as a druggable target (Albershardt et al, 2011).…”

Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting

“…Our focus on MCL-1 as a proof of concept for our strategy was rooted at the -helical nature of confirmed inhibitors and the challenging character of targeting this interface with small molecules. Recently, several potent and selective MCL-1 inhibitors have been reported, some of which have entered clinical trials (NCT03218683, NCT03672695, NCT02979366, NCT02675452, and NCT03797261) (65)(66)(67). As our study sought to explore the Alphabody's potential within a therapeutically relevant scenario rather than developing a novel anticancer drug candidate, we refrained from doing head-tohead comparisons with known MCL-1 inhibitors.…”