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Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. Significance: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. See related video: https://vimeo.com/720726054 This article is highlighted in the In This Issue feature, p. 1397

The YAP-TEAD protein-protein interaction (PPI) is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Current advanced pharmacological agents which aim at inhibiting YAP-TEAD oncogenic function do so by engaging into the lipid pocket of TEAD. Thereby the consequences of a direct pharmacological disruption of the interface of YAP and TEADs remain unexplored. Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter in clinical trial. The path to drug discovery was established by structure-based optimization of a truncated natural YAP peptide allowing the pharmacophore mapping of TEAD coil binding site. Based on in silico screening, validated hit was optimized using structure- and property-based lead optimization yielding IAG933, whose chemical structure will be for the first time disclosed here. Biochemical and cellular assays demonstrate that IAG933 specifically abrogates the interaction between YAP/TAZ coactivators and all four TEAD isoforms, thus selectively inhibiting TEAD-driven transcriptional activity and inducing anti-cancer effects. At the epigenome level, YAP eviction from chromatin was observed upon treatment with IAG933, while leaving TEADs genomic occupancy unaffected. Concomitantly, engagement of co-repressor VGLL4 translated to a decrease in enhancer activity with rapid and progressive changes in transcription of Hippo target genes. In preclinical experiments, IAG933 linear pharmacokinetics was consistent with dose proportional TEAD transcriptional inhibition and anti-tumor efficacy in xenograft and primary-tumor derived malignant pleural mesothelioma models. Daily treatment with IAG933 elicited complete tumor regression in the MSTO-211H xenograft model at well-tolerated doses. In line with the current clinical strategy for IAG933, robust anti-tumor efficacy in cancer models bearing NF2 loss of function or expressing TAZ-fusions was observed. Moreover, we provide evidence for combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a rationale of progressing IAG933 as a monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat patient populations of high unmet medical need. Citation Format: Tobias Schmelzle, Emilie Chapeau, Daniel Bauer, Patrick Chene, Jason Faris, Cesar Fernandez, Pascal Furet, Giorgio Galli, Jiachang Gong, Stephanie Harlfinger, Francesco Hofmann, Eloisa Jimenez Nunez, Joerg Kallen, Thanos Mourikis, Laurent Sansregret, Paulo Santos, Clemens Scheufler, Holger Sellner, Markus Voegtle, Markus Wartmann, Peter Wessels, Frederic Zecri, Nicolas Soldermann. IAG933, a selective and orally efficacious YAP1/WWTR1(TAZ)-panTEAD protein-protein interaction inhibitor with pre-clinical activity in monotherapy and combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB319.

Background: Oncogenic mutations occurring in the KRAS component of the RAS/MAPK pathway slow nucleotide cycling between its active (GTP-bound) and inactive (GDP-bound) states, shifting it towards the active state and increasing oncogenic signaling. Among these mutations, the glycine-to-cysteine mutation of amino acid 12 (KRASG12C), found in ~13% of non-small cell lung cancer (NSCLC) and ~4% of colorectal cancer (CRC), can be specifically targeted and irreversibly locked in the inactive state by covalent modification of Cys12. We have previously reported the discovery and preclinical profile of JDQ443, a selective, oral, covalent inhibitor of KRASG12C that binds under the Switch II loop. Here, we report its antiproliferative and antitumor activity against panels of cancer cell lines as well as cell- (CDX) and patient-derived (PDX) tumor xenografts. Methods: JDQ443 antiproliferative activity was assessed by a high-throughput cell viability assay in a large panel of KRASG12C (n=17) and non-G12C (n=233) cell lines. Single-agent antitumor activity was assessed against a panel of KRASG12C CDX models from NSCLC (LU99, H2122, H2030, and HCC44), pancreatic (Mia PaCa-2), and esophageal (KYSE410) cancer cell lines, plus one non-G12C lung line (H441; KRASG12V). JDQ443 in vivo activity against a panel of KRASG12C NSCLC (n=10) and CRC (n=9) PDX models was assessed either as a single agent or in combination with TNO155 (SHP2 inhibitor [i]), trametinib (MEKi), or ribociclib (CDK4/6i). In vivo combination studies with TNO155 were also performed in CDX models (LU99, H2030, HCC44, and KYSE410). Results: In vitro, JDQ443 demonstrated potent antiproliferative activity selectively towards KRASG12C cell lines. Dose-dependent tumor growth inhibition/regression was observed for all KRASG12C CDX models, but not for the H441 KRASG12V model, and was independent of once-daily (QD) or twice-daily (BID) dosing. Single-agent antitumor activity (best average response, duration of reduction in tumor doubling time) was observed across both PDX panels and was improved by all three combination treatments. The JDQ443/TNO155 combination improved single-agent activity across CDX models, with comparable antitumor benefit maintained at QD or BID TNO155 schedules in two of three models (LU99 and KYSE410). Combination with TNO155 allowed a reduced dose of JDQ443 to achieve similar target occupancy and antitumor activity versus JDQ443 alone. Conclusions: JDQ443 demonstrates significant activity against a broad range of KRASG12C solid tumor models, both in vitro and in vivo, that is increased when combined with agents targeting both upstream and downstream components of the RAS signaling pathway. The combination benefit of JDQ443 + TNO155 over JDQ443 alone is maintained at reduced doses for both agents. Citation Format: Andreas Weiss, Hans Voshol, Diana Graus Porta, Carmine Fedele, Dario Sterker, Ruben De Kanter, Rowan Stringer, Toni Widmer, Alice Loo, Daniel A. Guthy, Kim S. Beyer, Nils Ostermann, Catherine LeBlanc, Marc Gerspacher, Andrea Vaupel, Richard Sedrani, Frederic Zecri, Saveur-Michel Maria, Francesco Hofmann, Peter Hammerman, Jeff Engelman, Edwige Lorthiois, Simona Cotesta, Saskia M. Brachmann. JDQ443, a covalent inhibitor of KRASG12C with a novel binding mode, shows broad antitumor activity in KRASG12C preclinical models as a single agent and in combination with inhibitors of SHP2, MEK or CDK4/6 [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 4026.

RAS is the most frequently mutated oncogene in cancer. KRAS G12C mutations are most prevalent in lung adenocarcinoma (~13%) and colorectal adenocarcinoma (~4%), and occur less commonly in other solid tumor malignancies. First generation KRASG12C inhibitors show anti-tumor activity in early phase clinical trials. However, the emergence of resistance, mediated at least in part by RAS gene mutations that disrupt inhibitor binding and reactivation of downstream pathways, limit the duration of response. Here we report the identification of JDQ443 (NVP-JDQ443), a novel KRASG12C inhibitor which binds under the switch II loop with a novel binding mode, exploiting unique interactions with the KRASG12C protein compared to sotorasib and adagrasib. JDQ443 potently inhibits KRASG12C cellular signaling and proliferation in a mutant selective manner by irreversibly trapping the GDP-bound state of KRASG12C through formation of a covalent bond with cysteine at position 12. Consistent with its mechanism as an irreversible inhibitor, JDQ443 shows sustained target occupancy (TO) in vivo (KRASG12C TO t1/2 ~ 66 h in the MiaPaCa2 model) despite a blood half-life of ~ 2 hours, and exhibits a linear PK/PD relationship. JDQ443 has dose-dependent anti-tumor activity in mice bearing KRAS G12C mutated tumor xenografts comparable to sotorasib and adagrasib. In mouse, rat, and dog, JDQ443 is orally bioavailable, achieves exposures in a range predicted to confer anti-tumor activity, and is well-tolerated. Continuous delivery of JDQ443 using mini-pump administration demonstrates that area under the curve (AUC), rather than maximal concentration (Cmax), is the driver of efficacy. Combination of JDQ443 with the SHP2 inhibitor TNO155 further increases KRAS G12C target occupancy in vivo, enhanced pre-clinical anti-tumor activity, and delayed the emergence of resistance in xenografts. A genome-wide CRISPR screen in 5 KRAS G12C mutated lung cancer cell lines identifies novel mechanisms of resistance to the KRAS/SHP2 drug combination. Furthermore, the characterization of JDQ443 alone and in combination with TNO155 in BaF/3 pools addicted to KRAS alleles that have previously been shown to mediate resistance to adagrasib in clinical samples will be discussed. Collectively, these data show that JDQ443 is a potent, mutant-selective, covalent irreversible KRASG12C inhibitor with favorable pharmaceutical properties. A phase Ib/II clinical trial of JDQ443 alone and in combination with TNO155 in patients with advanced solid tumors harboring the KRAS G12C mutation is ongoing (NCT04699188). Citation Format: Saskia M. Brachmann, Andreas Weiss, Daniel A. Guthy, Kim Beyer, Johannes Voshol, Michel Maira, Anirudh Prahallad, Diana Graus Porta, Christian Schnell, Nils Ostermann, Andrea Vaupel, Marc Gerspacher, Catherine Leblanc, Dirk Erdmann, Dario Sterker, Grainne Kerr, Giovannoni Jerome, Victoria Head, Rowan Stringer, Ruben De Kanter, Kearns Jeff, Danielle Roman, Toni Widmer, Peter Wessels, Eloisa Jimenez Nunez, Richard Sedrani, Frederic Zecri, Francesco Hofmann, Jeff Engleman, Edwige Lorthiois, Simona Cotesta. JDQ443, a covalent irreversible inhibitor of KRAS G12C, exhibits a novel binding mode and demonstrates potent anti-tumor activity and favorable pharmacokinetic properties in preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P124.