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Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.

Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan‐FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR‐addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR‐amplified cell lines suggests that the anti‐proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756)., What's new? Deregulated fibroblast growth factor receptor (FGFR) signaling is involved in tumorigenesis and cancer progression. Here, the authors report on a novel pan‐FGFR inhibitor, rogaratinib, that potently and highly selectively prevents the activity of FGFRs 1, 2, 3, and 4. Rogaratinib inhibits cell proliferation in various FGFR‐addicted cancers in vitro, including colon, lung, and bladder cancer. Rogaratinib also exhibits strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR mRNA overexpression with good tolerability. Altogether, these data warrant the further development of rogaratinib for treatment of cancers with FGFR alterations, and clinical trials are currently ongoing.

The PI3K-AKT-mTOR signaling cascade is activated in the majority of human cancers, and its activation also plays a key role in resistance to chemo and targeted therapeutics. In particular, in both breast and prostate cancer, increased AKT pathway activity is associated with cancer progression, treatment resistance and poor disease outcome. Here, we evaluated the activity of a novel allosteric AKT1/2 inhibitor, BAY 1125976, in biochemical, cellular mechanistic, functional and in vivo efficacy studies in a variety of tumor models. In in vitro kinase activity assays, BAY 1125976 potently and selectively inhibited the activity of full-length AKT1 and AKT2 by binding into an allosteric binding pocket formed by kinase and PH domain. In accordance with this proposed allosteric binding mode, BAY 1125976 bound to inactive AKT1 and inhibited T308 phosphorylation by PDK1, while the activity of truncated AKT proteins lacking the pleckstrin homology domain was not inhibited. In vitro, BAY 1125976 inhibited cell proliferation in a broad panel of human cancer cell lines. Particularly high activity was observed in breast and prostate cancer cell lines expressing estrogen or androgen receptors. Furthermore, BAY 1125976 exhibited strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CAH1074R mutant), the MCF7 and HBCx-2 breast cancer models and the AKTE17K mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models. These findings indicate that BAY 1125976 is a potent and highly selective allosteric AKT1/2 inhibitor that targets tumors displaying PI3K/AKT/mTOR pathway activation, providing opportunities for the clinical development of new, effective treatments.

Introduction: The critical role of cyclin-dependent kinases in cell division and gene transcription has made them targets for anti-cancer therapies. Positive transcription elongation factor b (PTEFb)/cyclin-dependent kinase 9 (CDK9) plays a key role in transcription of short-lived anti-apoptotic survival proteins and oncogenes such as MYC and MCL-1. BAY 1251152 (BAY) is a potent and highly selective second generation PTEFb/CDK9 inhibitor. We report here the results of a phase I study to determine the safety, tolerability, pharmacokinetics (PK), maximum tolerated dose and preliminary anti-tumor activity of BAY in patients with AML. Methods: Patients with confirmed AML who are refractory to or have exhausted all available therapies were eligible. A minimum of 3 and a maximum of 9 patients were to be enrolled per dose level in a sequential dose escalation design. BAY was administered intravenously over 30 minutes once weekly for 21-day cycles. PK was assessed at cycle-1, day 1/D8/D15. Dose-limiting toxicities (DLTs) for hematologic events were defined as prolonged grade (G) 4 neutropenia and/or G3 thrombocytopenia and/or any G5 event. DLTs for non-hematological toxicity were any G3-G5 event not clearly resulting from underlying malignancy, among others. Responses were evaluated using Cheson (2003) criteria. Adverse events (AEs) were assessed using CTCAE v4.03. Results: A total of 30 patients were enrolled, 9 of whom failed screening. Twenty one patients received treatment with BAY in 4 dose cohorts: 5, 10, 20, and 30 mg. The median age was 66 (range 20-79), with 62% being male. The median number of prior lines of therapy was 3 (range 1 - 6). Four patients were treated per dose cohorts 1-3 without occurrence of DLTs. Nine patients were treated in cohort 4 (30 mg) and were evaluable for safety, with 7 evaluable for response. Nine patients (43%) discontinued treatment due to clinical progression, 19% due to withdrawal by subject, 19% due to lack of efficacy, 14% due to an AE associated with disease progression. A MTD was not defined. PK assessment indicated that the mean elimination half-life was 3-9 hours with no accumulation over multiple doses. The mean AUC of the 30 mg cohort was within the expected therapeutic exposure range based on preclinical studies. Interestingly, pharmacodynamic assessment of MYC, MCL-1 and PCNA mRNA in whole blood indicated that BAY treatment led to significant, but short-lived, reductions; highest degree of down-regulation was achieved 0.5-4 hours post-dose for MYC, 1-3 hours post-dose for MCL-1, and 1-4 hours post-dose for PCNA. However, no objective responses were observed, with only modest reductions in bone marrow blasts in some patients. In the 30 mg cohort, the longest treatment duration was 63 days. Single patients in each of cohorts 1-3 exceeded this duration but only minimally. Overall treatment-emergent G3/G4 AEs recorded in >10% of patients included anemia (G3 26.7%/G4 6.7%), lung infection (G3 23.3%), neutrophil count decreased (G4 20%), febrile neutropenia (G3 13.3%), and leukocytosis (G3 10%). Clinical laboratory assessments in cohort 4 indicated that 7 of 9 patients (78%) had G4 neutrophil count decreased and G3 anemia, and 5 of 9 (56%) had platelet count decreased. G5 events included 2 each for sepsis and cardiac arrest, and 1 patient with leukocytosis; none of the G5 events were considered related to the study treatment. Conclusions: Treatment of AML patients with BAY did not result in objective responses despite achieving drug levels in the expected therapeutic range and evidence of target engagement. Given the good tolerability and on-target activity, BAY 1251152 might be a good candidate for future combination therapies. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Amgen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Fusion Pharma: Consultancy, Research Funding; Novartis: Consultancy. Scholz:Bayer: Employment. Ince:Bayer: Employment. Valencia:Bayer: Employment. Souza:Bayer: Employment.

The PI3K-AKT-mTOR signaling cascade is activated in the majority of human cancers, and its activation also plays a key role in resistance to chemo and targeted therapeutics. In particular, in both breast and prostate cancer, increased AKT pathway activity is associated with cancer progression, treatment resistance and poor disease outcome. Here, we evaluated the activity of a novel allosteric AKT1/2 inhibitor, BAY 1125976, in biochemical, cellular mechanistic, functional and in vivo efficacy studies in a variety of tumor models. In in vitro kinase activity assays, BAY 1125976 potently and selectively inhibited the activity of full-length AKT1 and AKT2 by binding into an allosteric binding pocket formed by kinase and PH domain. In accordance with this proposed allosteric binding mode, BAY 1125976 bound to inactive AKT1 and inhibited T308 phosphorylation by PDK1, while the activity of truncated AKT proteins lacking the pleckstrin homology domain was not inhibited. In vitro, BAY 1125976 inhibited cell proliferation in a broad panel of human cancer cell lines. Particularly high activity was observed in breast and prostate cancer cell lines expressing estrogen or androgen receptors. Furthermore, BAY 1125976 exhibited strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CA

2507Background: PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MYC and MCL-1 plays a critical role in a variety of cancers. We present findings...

Background: Fibroblast growth factor receptor (FGFR)-mediated pathways are considered to be promising anticancer therapy targets. There are several types of genetic evidence that support an oncogenic function of FGFRs: identification of gene amplifications, activating mutations, chromosomal translocations, and aberrant splicing at the post-transcriptional level. Since FGFR expression is regulated not only by genetic but also by epigenetic mechanisms, examination of tumor FGFR mRNA levels may identify cancer patients likely to benefit from rogaratinib (BAY 1163877), an oral, potent small-molecule pan-FGFR inhibitor. We conducted a phase I study of rogaratinib in Japanese subjects with refractory, locally advanced or metastatic solid tumors selected by elevated tumor FGFR1-3 mRNA expression to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy (NCT02592785). Methods: Japanese subjects were enrolled at 600 mg BID (Cohort1) or 800 mg BID as the recommended phase 2 dose (Cohort 2) on a continuous 21-day cycle based on high FGFR1-3 mRNA expression. Archival or newly obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples were analyzed for elevated FGFR1-3 mRNA levels by RNA in situ hybridization (RNAscope®; Advanced Cell Diagnostics, Inc., Newark, CA) and Nanostring® assay (NanoString Technologies, Inc., Seattle, WA). Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: In the prescreening phase of this study, 62 FFPE samples from cancer patients with several tumor types were assessed for FGFR1-3 tumor mRNA expression levels and the valid prescreening results were obtained from 48 samples. Among them, 16 samples (16/48, 33%) were found to overexpress FGFR mRNA. Overall, 9 FGFR mRNA-positive patients were enrolled and treated with rogaratinib, 3 in Cohort 1 and 6 in Cohort 2. All subjects had experienced more than one adverse event (AE). Most of them were Grade 1 or 2. No DLT, no SAE, no Grade 4 or 5 AEs were reported. Two G3 drug-related AEs were hyponatremia and increased ALT. The most common treatment related AE was hyperphosphatemia with Grade 1 or 2 and all cases were controllable with anti-hyperphosphatemia treatment. PK exposure in Japanese subjects was comparable to Western subjects. Eight patients could be advanced to at least one tumor response assessment by CT imaging. As a result, 1 patient with epipharynx cancer achieved a partial response (PR) while 5 patients had stable disease (SD) as best response in target lesions, including three SD patients with tumor shrinkage compared to baseline CT imaging. Conclusions: Rogaratinib showed a good tolerability with a confirmed PR and a disease control rate (DCR) of 56% (5/9). We concluded that 800 mg BID is safe and well tolerable to Japanese patients confirming the global recommended dose. The high prevalence of FGFR mRNA overexpression in tumors as well as the clinical response of FGFR-positive tumors support an mRNA-based patient selection for FGFR inhibitor treatment of cancer. Citation Format: Makoto Tahara, Shunji Takahashi, Matthias Ocker, Stuart Ince, Hendrik Nogai, Changliang Zhang, Fumiyoshi Sei, Peter Ellinghaus. Safety, tolerability, pharmacokinetics, and efficacy of pan-fibroblast growth factor receptor inhibitor rogaratinib in Japanese patients with refractory, locally advanced metastatic solid tumors selected with a novel, mRNA-based patient selection strategy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A099.

BAY 1163877 is a potent and selective, oral, small molecule pan-FGFR inhibitor with anti-tumor activity in a wide range of cancer types. In vivo profiling in xenograft models identified tumor FGFR mRNA levels as a predictor of drug efficacy. Anti-tumor efficacy was largely independent of the tumor type surveyed or the FGFR isoform being overexpressed. Preclinical models included a patient-derived squamous head and neck cancer (HNSCC) xenograft (PDx) model overexpressing FGFR3 mRNA, a bladder cancer PDx model overexpressing FGFR2 mRNA, and a squamous esophageal cancer PDx model overexpressing FGFR1 mRNA. Against this background, clinical proof-of-concept was assessed by enrolling patients into the stratified expansion cohort of a Phase 1 study of BAY 1163877 (NCT01976741) based on tumor FGFR1-3 mRNA levels. FGFR1-3 mRNA was quantified in archival or newly obtained FFPE tumor biopsies by RNA in situ hybridization (RNAscope, ACD) and digital transcript counting (NanoString). In total, biopsies from > 500 patients were studied for FGFR1-3 mRNA expression levels. Based on preclinical xenograft experiments showing that low to moderate FGFR1-3 mRNA overexpression was not sufficient for a robust drug response, only patients with an RNAscope score of 3 or 4 (range 0-4) or a normalized Nanostring signal of 800 counts were eligible for enrollment. By applying these stringent criteria, FGFR1-3 mRNA positivity was on average observed with a 2- to 3-fold higher prevalence than published data for genetic aberrations of FGFRs in the respective tumor types (including amplifications, translocations, mutations). We further identified FGFR mRNA(+) tumor types in which genetic FGFR aberrations have not been previously reported. FGFR1-3 mRNA positivity ranged from 10% in lung adenocarcinoma to 45% in squamous non-small cell lung cancer (sqNSCLC) and 54% in HNSCC. As of August 2016, 57 FGFR mRNA(+) patients were enrolled and treated with BAY 1163877. Six patients experienced a partial remission (PR) by RECIST v1.1 criteria; including an FGFR3 mRNA(+) HNSCC patient without FGFR3 amplification or translocation, an FGFR1 mRNA(+) adenoid cystic carcinoma patient, and an FGFR1 mRNA(+) sqNSCLC patient (both without FGFR1 gene amplification), as well as an FGFR3 mRNA(+) bladder cancer patient without FGFR3 amplification, mutation or translocation. These results suggest that high FGFR1-3 mRNA expression identifies patients sensitive to FGFR inhibition. This population includes patients with and without genetic aberrations of FGFR1-3 encoding genes. In summary, an mRNA expression-based selection approach may identify a broader patient population with potential benefit from BAY 1163877, including tumor types not previously associated with altered FGFR signaling. Citation Format: Peter Ellinghaus, Matthias Ocker, Sebastian Bender, Christoph Kneip, Stuart Ince, Markus Joerger, Martin Schuler. Use of tumor mRNA expression for patient selection in a phase I study of the pan-fibroblast growth factor receptor inhibitor BAY 1163877 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3738. doi:10.1158/1538-7445.AM2017-3738

PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins like Mcl-1 and Myc plays a critical role in cancer cell growth and survival in various tumor entities including AML. In addition, these survival proteins play important roles in the development of resistance to chemotherapy. We previously disclosed the preclinical profile of BAY 1143572, the first selective, orally available PTEFb/CDK9 inhibitor that entered clinical development [1-3]. BAY 1143572 had low nanomolar activity against PTEFb/CDK9, an at least 50-fold selectivity against other CDKs in enzymatic assays and broad anti-proliferative activity against a panel of tumour cell lines with sub-micromolar IC50 values. BAY 1143572 also showed single agent in vivo efficacy at tolerated doses in various xenograft tumour models in mice and rats upon once daily oral administration. To fully explore future treatment options using selective PTEFb/CDK9 inhibitors we initiated a follow-up program to identify novel PTEFb/CDK9 inhibitors for treatment of cancer with increased potency enabling i.v. treatment of patients. Extensive lead optimisation efforts, including various scaffold hops, led to the identification of BAY 1251152. In comparison to oral BAY 1143572, BAY 1251152 shows significantly increased biochemical (IC50 CDK9 = 3 nM) and cellular potency (IC50 MOLM13 = 29 nM), increased selectivity against CDK2 as well as high permeability and no efflux. The significantly reduced therapeutic dose and high solubility of BAY 1251152 enable the desired i.v. application. BAY 1251152 demonstrated excellent efficacy upon i.v. treatment in xenograft models (e.g. MOLM13) in mice and rats. BAY 1251152 is currently being evaluated in Phase I studies (NCT02635672; NCT02745743) to determine the safety, tolerability, pharmacokinetics and initial pharmacodynamic biomarker response in patients with advanced cancer. This presentation will highlight the key learnings from our PTEFb/CDK9 i.v. lead optimization program and disclose the structure of BAY 1251152 for the first time. [1]: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3022. [2]: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2015-DDT02-02. [3]: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2828. doi:10.1158/1538-7445.AM2015-2828 Citation Format: Ulrich T. Luecking, Arne Scholz, Dirk Kosemund, Rolf Bohlmann, Hans Briem, Philip Lienau, Gerhard Siemeister, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Michael Brands. Identification of potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer: from p.o. to i.v. application via scaffold hops [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 984. doi:10.1158/1538-7445.AM2017-984

386 Background: FGFRs play a role in a variety of malignancies, including urothelial bladder cancer (UBC). Whereas genetic alterations of FGFRs in UBC are known, non-genetic and epigenetic activation of FGFR gene expression have also been described. BAY 1163877 is an oral inhibitor of FGFRs 1-3 with antitumor activity in FGFR mRNA overexpressing xenograft models not limited to DNA alterations. We report the results from a phase I expansion cohort in UBC patients pre-screened for treatment with BAY 1163877 based on FGFR1-3 mRNA overexpression and/or activating mutations in the FGFR3 gene. Methods: FGFR mRNA levels were assessed in paraffin-embedded archival or fresh biopsy specimens by RNAscope and NanoString technology and activating mutations by RT-PCR-based mutation assay. Tumor response to treatment was assessed by RECIST, v1.1. Adverse events were assessed using CTCAE v4.03 criteria. Results: A total of 80 patients from multiple indications were enrolled in the phase I study; 800 mg BID was established as the recommended phase 2 dose. Sixty seven UBC patients were screened, with 31 tumor biopsies (46%) determined to overexpress FGFR mRNA: 2 patients each with FGFR1 and FGFR2, and 27 patients with FGFR3. Of the 27 patients with FGFR3 mRNA overexpression, 5 had in parallel an activating mutation in FGFR3 gene. Eight UBC patients met eligibility criteria and entered treatment; all had elevated FGFR3 mRNA expression and 4 had alterations in FGFR3 DNA (3 mutations and 1 translocation). Seven patients (87.5%) had tumor shrinkage in target lesions as best response, with 3/8 partial responses (PR; 37.5%). One patient with a PR presented with elevated FGFR3 mRNA without evidence of aberrant DNA. BAY 1163877 was generally well tolerated and AEs manageable with dose modification. The most common AEs in the overall population were increased phosphorus (66% all grade, 1 grade-3 event) and diarrhea (33% all grade, 2 grade-3 events). Conclusions: Selection of patients for treatment with BAY 1163877 based on FGFR mRNA expression levels in archival tissue was feasible. BAY 1163877 had a favorable safety profile and promising anti-tumor activity in UBC patients. Clinical trial information: NCT01976741.

The PI3K-AKT-mTOR signaling cascade is one of the major drivers in the development of cancer. It is constitutively activated in many types of cancers and is one of the prominent pathways that promote tumor cell survival and confers resistance to antihormonal therapies for patients with breast cancer. Breast cancer has been classified into at least four distinct subtypes, based on molecular profiling. Luminal-B breast cancer, although still expressing the hormone receptor, has been identified as relatively insensitive to endocrine therapy and is an entity with highest need for novel treatments and combination approaches. Despite the notable improvements in endocrine therapy, the invariable appearance of endocrine resistance, either primary or secondary, remains an important issue in this type of tumor. Main cancer signaling pathways, including PI3K/Akt/mTOR and CCND1/CDK4-6, are thought to play an important role in development of this resistance. Therefore AKT is considered an attractive drug target for the treatment of breast cancer. BAY 1125976, an orally active, potent, highly selective, allosteric AKT1/2 inhibitor is currently in phase I clinical development (NCT01915576). BAY 1125976 is particularly effective in preclinical models with PI3K-AKT pathway aberrations and luminal B status as shown by profiling in a panel of tumor cell lines as well as respective in vivo studies. The efficacy of BAY 1125976 in inhibition of cell proliferation is correlated with luminal status of the tumor as shown in several cell line panels. In vitro combination with anti-hormonal therapeutics showed synergistic anti-proliferative effects and rendered resistant cell lines sensitive towards tamoxifen or fulvestrant treatment. In the MCF-7 cell line tamoxifen combined with BAY 1125976 resulted in a 14 fold reduction of the IC50 for inhibition of cell proliferation compared to monotherapy. This translated into additive to synergistic activity in combination with tamoxifen in a ER+ MCF7 (PIK3CAE545K) BC model and enabled the use of alternative dosing schedules with improved efficacy versus monotherapy. BAY 1125976 also showed potent inhibition of tumor cell growth in a tamoxifen- and fulvestrant-resistant derivate of MCF-7 enabling a reduction of the therapeutic dose of BAY 1125976 and thereby improving tolerability while keeping efficacy. Combination of the allosteric AKT inhibitor BAY 1125976 therefore provides an interesting opportunity in improving efficacy of antihormonal therapy in luminal B type breast cancer. Citation Format: Oliver Politz, Lars Baerfacker, Stuart Ince, Andrea Haegebarth, Ningshu Liu, Roland Neuhaus, Ulf Boemer, Martin Michels, Karl Ziegelbauer, Dominik Mumberg. Allosteric AKT1/2-inhibitor BAY 1125976 as potent inhibitor in luminal breast cancer resistant to antihormone therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 379.

BET proteins recognize histone acetylation marks and play an essential role in transcription elongation. BRD4, the best studied family member, binds to the regulatory regions of oncogenes such as MYC, thereby controlling its expression and that of the downstream transcriptome. Following the identification of the first selective inhibitors, BET proteins have been shown to play essential roles in hematological and, more recently, in solid tumors. Here we studied the efficacy of the novel BET inhibitor BAY 1238097 in melanoma models. BAY 1238097 was a potent BET inhibitor with IC50 values of 47 and 295 nM for BRD4 BD1 and BD2, respectively. In NanoBRET assays, the interaction between BRD4, BRD3 or BRD2 with histone H4 was blocked in intact cells with IC50 values of 65 nM, 294 nM and 642 nM, respectively. In addition to its strong anti-proliferative activity in several hematological tumor models, BAY 1238097 was also effective in several melanoma cell lines with GI50 values below 500 nM in BRAF wild-type (CHL-1, COLO-792, B16F10, IPC-298, MeWo) as well as BRAF mutant (A375, G-361, SK-MEL-30, LOX-IMVI, SK-MEL-5, MEL-HO) models. Resistant cell lines with GI50 values above 10 μM were identified in both the BRAF wild-type and mutant groups. ChIP analysis performed in BRAF wild-type CHL-1 cells showed that BAY 1238097 displaced BRD4 from regulatory regions of oncogenes such as MYC, leading to loss of expression. The oxygen consumption rates of the melanoma cell lines were measured and we found that cell lines sensitive to BAY 1238097 depended on oxidative phosphorylation rather than glycolysis for energy production. In vivo efficacy was determined for BAY 1238097 in three patient-derived melanoma models harboring the wild-type BRAF gene. Daily, oral treatment with 7.5 mg/kg BAY 1238097 led to significantly reduced tumor growth (39% T/C) in one model. Interestingly, this model was resistant to dacarbazine given i.p. at 100 mg/kg daily. No biologically significant anti-tumor activity was observed for the two other models treated with the same conditions (62% and 70% T/C, respectively). Altogether the results show BAY 1238097 to be a potent inhibitor of BRD4 binding to histones. The compound has strong anti-proliferative activity in different melanoma models, regardless of the BRAF mutation status but related to the metabolic activity. One out of three patient-derived melanoma models with wild-type BRAF responded to BAY 1238097 treatment in vivo. Future studies will help to better characterize the impact of BET inhibition on melanoma. Citation Format: Bernard Haendler, Kathy A. Gelato, Laura Schöckel, Tatsuo Sugawara, Pascale Lejeune, Heidrun Ellinger-Ziegelbauer, Amaury E. Fernandez-Montalvan, Simon Holton, Stephan Siegel, Melanie Heroult, Annette Walter, Stuart Ince, Matthias Ocker. The BET inhibitor BAY 1238097 shows efficacy in BRAF wild-type and mutant melanoma models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4703.

PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins like Mcl-1 and Myc, plays a critical role in cancer cell growth and survival in various tumor entities including AML. In addition, these survival proteins exhibit important functions in the development of resistance to chemotherapy. In contrast to pan-CDK inhibitors, to our knowledge PTEFb selective inhibitors have not been explored for clinical utility. We report the preclinical activity of BAY 1143572, a novel selective PTEFb/CDK9 inhibitor (AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-02) currently being investigated in Phase I clinical trials in advanced cancer (NCT01938638) and acute leukemia (NCT02345382) in various in vitro, ex vivo and in vivo models of AML. BAY 1143572 inhibited the proliferation of 7 MLL-rearrangements positive and negative AML cell lines with a median IC50 of 385 nM (range 230-1100 nM) and induced apoptosis. Furthermore, BAY 1143572 showed potent in vitro activity in 8 out of 10 non-MLL-rearranged patient derived AML samples incl. NPM1 mutant and Flt3-ITD positive samples derived from intermediate and high risk patients. Moreover, we elucidated the dynamic changes of the cellular proteome/phosphoproteome upon pharmacological and genetic PTEFb inhibition and identified PTEFb interaction partners in various AML in vitro models. These analyses uncover the oncogenic PTEFb-dependent signaling networks and substantiate the molecular rationale for the use of PTEFb inhibitors in this indication. When applied in vivo, BAY 1143572 exhibited single agent efficacy at tolerated doses in 4 out of 5 AML xenograft tumor models in mice and in 2 out of 2 AML xenograft tumor models in rats upon once daily oral administration. Of note, partial or even complete remissions could be achieved in several models. Furthermore, intermittent dosing schedules with up to 4 days treatment pauses were feasible in terms of efficacy and tolerability. Using MOLM-13 xenografts in mice and rats to address the in vivo MoA of BAY 1143572, a transient inhibition of RNA polymerase II phosphorylation, MYC mRNA and protein levels, MCL-1 mRNA and protein levels, and an induction of apoptosis was documented. In conclusion, our data provide the rationale for the initiation of clinical development of BAY 1143572 as a potent and highly selective inhibitor of PTEFb/CDK9 with first-in-class potential for the treatment of AML patients. A phase I clinical trial to determine the safety, tolerability and recommended Phase 2 dose in this indication is ongoing (NCT02345382). Citation Format: Arne Scholz, Thomas Oellerich, Akhtar Hussain, Sarah Lindner, Ulrich Luecking, Annette O. Walter, Peter Ellinghaus, Ray Valencia, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Stuart Ince, Hubert Serve, Karl Ziegelbauer. BAY 1143572, a first-in-class, highly selective, potent and orally available inhibitor of PTEFb/CDK9 currently in Phase I, shows convincing anti-tumor activity in preclinical models of acute myeloid leukemia (AML). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3022.

Squamous cell carcinoma (SCC) is a common subtype of lung cancer and is strongly associated with smoking. In contrast to adenocarcinomas of the lung, SCCs do not significantly harbor epidermal growth factor (EGFR) mutations or ALK, ROS1 or RET translocations, which are therapeutically tractable. SCC of the lung and SCC of the head and neck region and esophagus not only share risk factors, morphologic features and mechanisms of tumorigenesis but also frequent fibroblast growth factor receptor 1 (FGFR1) gene alterations. In addition, we found that FGFR2 and FGFR3 expression were also altered in patient derived models of SCC of various origins. FGFRs may thus represent viable therapeutic targets for the treatment of SCC. BAY 1163877, an orally available and potent inhibitor of FGFR1, FGFR2 and FGFR3, inhibited SCC cell proliferation as well as downstream FGFR signaling in vitro. When applied in vivo, BAY 1163877 was able to reduce growth of a FGFR1-overexpressing lung SCC xenograft model, a FGFR1-overexpressing esophageal SCC xenograft model, and a FGFR3-overexpressing head and neck SCC xenograft model, achieving reductions in tumor growth by 67 to 92% as compared to the vehicle control. BAY 1163877 was very well tolerated in all models performed. These data suggest that selective inhibition of FGFR1 to 3 with BAY 1163877 might have therapeutic potential for the treatment of SCC malignancies. A phase I clinical trial (NCT01976741) to determine the safety, tolerability and recommended Phase 2 dose in advanced cancer patients is ongoing. Citation Format: Mélanie Héroult, Matthias Ocker, Charlotte Kopitz, Dieter Zopf, Andrea Hägebarth, Karl Ziegelbauer, Stuart Ince, Peter Ellinghaus. Anti-tumor efficacy of the selective pan-FGFR Inhibitor BAY 1163877 in preclinical squamous cell carcinoma models of different origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2015-772

PTEFb (positive transcription elongation factor b) is a heterodimer of the transcriptional control kinase CDK9 (Cyclin-dependent kinase 9) and Cyclin T. PTEFb phosphorylates and activates RNA polymerase II. PTEFb inhibition causes rapid depletion of short-lived mRNA transcripts and their associated protein products involved in proliferation and survival like Myc, or Mcl-1 which results in cell death of addicted tumor cells. We previously disclosed the profile of the lead compound PTEFb BAY1, a nanomolar PTEFb inhibitor with 50-fold selectivity within the CDK family and cellular potency of about 1 μM in proliferation assays on various human tumor cell lines [1]. PTEFb BAY1 also revealed in vivo efficacy in a human acute myeloid leukemia (AML) xenograft model in nude mice. However, the lead compound also displayed certain limitations in ADME properties like low aqueous solubility and a strong recognition by efflux transporters in the Caco2 assay. Based on these findings, extensive lead optimisation efforts led to the rapid identification of BAY 1143572 which is a more potent and highly selective, orally available PTEFb inhibitor with first-in-class potential. BAY 1143572 has a high aqueous solubility, reduced drug efflux and a moderate oral bioavailability across species that allows daily as well as intermittent dosing schedules in animal models. BAY 1143572 revealed strong in vitro and in vivo anti-tumor efficacy with various cell-lines. BAY 1143572 is currently being evaluated in a Phase I study to determine the safety, tolerability, pharmacokinetics and initial pharmacodynamic biomarker response in patients with advanced cancer. This presentation will highlight the key learnings from our PTEFb lead optimization program. [1]: AACR, April 5-9, 2014, San Diego, Poster Presentation, Abstract 4538, Cancer Res October 1, 2014, 74:4538; doi:10.1158/1538-7445.AM2014-4538 Citation Format: Ulrich TJ Luecking, Arne Scholz, Philip Lienau, Gerhard Siemeister, Dirk Kosemund, Rolf Bohlmann, Knut Eis, Mark Gnoth, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Bert Klebl, Axel Choidas, Peter Nussbaumer, Matthias Baumann, Carsten Schultz-Fademrecht, Gerd Ruehter, Jan Eickhoff, Michael Brands. Rapid identification of potent and highly selective, oral PTEFb Inhibitor BAY 1143572 with first in class potential. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2828. doi:10.1158/1538-7445.AM2015-2828

PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins like MYC, a key oncogene in multiple tumors, plays a critical role in cancer cell growth and survival. In addition, these survival proteins exhibit important functions in the development of resistance to chemotherapy. In contrast to pan-CDK inhibitors which are currently evaluated in Phase I and II clinical trials, to our knowledge PTEFb selective inhibitors have not been explored for clinical utility. We report for the first time the preclinical profile and structure of BAY 1143572, a novel selective PTEFb/CDK9 inhibitor currently being investigated in a Phase I clinical trial. BAY 1143572 had potent and highly selective PTEFb-kinase inhibitory activity in the low nanomolar range against PTEFb/CDK9 and an at least 50-fold selectivity against other CDKs in enzymatic assays. Furthermore, BAY 1143572 showed a favorable selectivity against a panel of non-CDK kinases in vitro. The potent enzymatic activity on PTEFb translated into broad antiproliferative activity against a panel of tumor cell lines with sub-micromolar IC-50 values. In line with the proposed mode of action, a concentration-dependent inhibition of the phosphorylation of the RNA polymerase II and downstream reduction of MYC mRNA and protein levels was observed in vitro. This inhibition was accompanied by an induction of apoptosis in cellular assays. BAY 1143572 also showed single agent in vivo efficacy at tolerated doses in various xenograft tumor models in mice and rats upon once daily oral administration. Potent anti-tumor activity characterized with partial or even complete remissions could be documented in models showing different MYC gene alterations like amplifications and translocations. Treatment with BAY 1143572 resulted in a transient inhibition of intratumoral MYC mRNA and protein levels and an induction of apoptosis in these models. The inhibition of MYC mRNA was also observed in blood cells of BAY 1143572-treated rats indicating the potential clinical utility of MYC in blood cells as a pharmacodynamic marker in clinical development. The in vivo efficacy of BAY 1143572 was significantly enhanced in combination with several chemotherapeutics in different solid tumor models. These pharmacology data provided the rationale for the initiation of clinical development of BAY 1143572 in advanced cancer patients (NCT01938638). In conclusion, our data provide preclinical proof of concept for BAY 1143572 as a potent and highly selective inhibitor of PTEFb/CDK9 with first-in-class potential. Further clinical evaluation of BAY 1143572 for the treatment of cancers dependent on the transcription of the key oncogene MYC and other short-lived survival proteins is warranted. Citation Format: Arne Scholz, Ulrich Luecking, Gerhard Siemeister, Philip Lienau, Ulf Boemer, Peter Ellinghaus, Annette O. Walter, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. BAY 1143572: A first-in-class, highly selective, potent and orally available inhibitor of PTEFb/CDK9 currently in Phase I, inhibits MYC and shows convincing anti-tumor activity in multiple xenograft models by the induction of apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2015-DDT02-02

The family of cyclin-dependent kinase (CDK) proteins consists of multiple cell cycle regulating CDK members as well as members involved in the regulation of gene transcription like CDK9/PTEFb (positive transcription elongation factor b). Inhibition of PTEFb and its direct downstream target RNA polymerase II is thought to cause rapid depletion of short-lived mRNA transcripts of important survival proteins like c-myc and Mcl-1 and thereby to induce growth delay and apoptosis in addicted tumor cells. In contrast to pan-CDK inhibitiors which are currently evaluated in Phase I and II clinical trials, PTEFb selective inhibitors have not been explored for clinical utility. BAY 1112054 is a potent and highly selective PTEFb-kinase inhibitor with low nanomolar activity against PTEFb/CDK9 and an at least 50-fold selectivity against other CDKs in enzymatic assays. Furthermore, BAY 1112054 shows a favourable selectivity against non-CDK kinases in vitro. The compound exhibits broad anti-proliferative activity against a panel of tumor cell lines with sub-micromolar IC-50 values. In line with the proposed mode of action, a concentration-dependent inhibition of the phosphorylation of the RNA polymerase II was observed in A549 tumor cells. This inhibition was accompanied by a reduction of intracellular Mcl-1 protein levels. Furthermore, BAY 1112054 increased DNA fragmentation in synchronized HeLa cells upon compound treatment for 24 hours. BAY 1112054 showed convincing in vivo efficacy at tolerated doses in two xenograft models in mice. Once daily oral treatment led to complete tumor stasis in established MOLM-13 AML xenografts. Pharmacokinetic analysis revealed that unbound plasma levels were 8 to 12 hours above the cellular IC50 in this model. In vivo efficacy and tolerability of the once daily po schedule of BAY 1112054 was confirmed in NCI-H82 SCLC xenografts. Xenografted tumors of this model showed lower levels of RNA polymerase II phosphorylation and Mcl-1 upon treatment with BAY 1112054. In conclusion, our data provides in vitro and in vivo proof of concept for BAY 1112054, a potent and highly selective inhibitor of PTEFb/CDK9 with first-in-class potential, and warrant further clinical evaluation of PTEFb selective inhibitors for the treatment of cancers addicted to the transcription of short-lived anti-apoptotic survival proteins. Citation Format: Arne Scholz, Ulrich Lücking, Gerhard Siemeister, Philip Lienau, Knut Eis, Antje Wengner, Kirstin Petersen, Ulf Bömer, Peter Nussbaumer, Axel Choidas, Gerd Rühter, Jan Eickhoff, Carsten Schultz-Fademrecht, Bert Klebl, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Michael Brands, Karl Ziegelbauer. BAY 1112054, a highly selective, potent and orally available inhibitor of PTEFb/CDK9, shows convincing anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2014-4538

The PI3K-AKT-mTOR signaling cascade is activated in human cancers by elevated membrane receptor activity, mutation, amplification, and deletion of genes encoding components of the pathway. An oncogenic, single hotspot mutation in the AKT1 gene, G49A:E17K, in the pleckstrin homology domain of AKT1, was described in human cancers with highest relative incidence in breast cancer. The E17K mutation in AKT1 results in PI3K-independent membrane recruitment of AKT1. Recently we reported the development of a highly selective, potent allosteric AKT1/2 inhibitor BAY 1125976 with strong in vitro and in vivo activity in tumor models with activated AKT signaling and strong synergistic activity in combination. The efficacy of BAY 1125976 was evaluated in tumor models carrying activation of the PI3K-AKT pathway by either deletion of PTEN or activating mutation in PI3K. We investigated whether BAY 1125976 can also inhibit AKT signaling in cell lines carrying an activating mutation in AKT. To this extend, KU-19-19 (AKT1E17K; NRASQ61R) bladder cancer as well as LAPC4 (AKT1E17K) prostate cancer cell lines both bearing the AKT1E17K mutation were profiled. BAY 1125976 potently inhibited AKT activation as well as downstream signaling in KU-19-19 and LAPC4 cells. Furthermore, anti-tumor efficacy of BAY 1125976 was tested in the patient-derived anal cancer xenograft AXF 984 (AKT1E17K). BAY 1125976 shows dose-dependent potent pathway activity in AKT1mut patient derived tumor model with inhibition of pAKT473 as well as downstream targets p- PRAS40 and p-FOXO3a compared to selected PI3K, AKT and mTOR inhibitors. Continuous daily treatment of AXF 984 (AKT1E17K) mouse xenografts with 25 mg/kg and 50 mg/kg QD p.o. BAY 1125976 resulted in very potent statistically significant anti-tumor efficacy. All animals of these treatment groups exhibited tumor shrinkage or disease control with response rates of 88% and 83%, respectively. Furthermore, for animals treated with 50 mg/kg BAY 1125976 the delay of reaching a relative tumor volume of 600% was statically significant compared to the vehicle-treated control group. In summary, BAY 1125976 showed superior anti-tumor activity in AKT1E17K mutated models compared to PI3K and mTOR inhibitors. These results indicate that the clinical development of BAY 1125976 in patients with activating mutation in AKT could result in an innovative and more effective alternative to current treatments. Citation Format: Oliver Politz, Arne Scholz, Andrea Haegebarth, Ningshu Liu, Lars Baerfacker, Stuart Ince, Roland Neuhaus, Ulf Boemer, Martin Michels, Dominik Mumberg. BAY 1125976, is a selective allosteric AKT1/2 inhibitor with high efficacy in AKT1-mutated cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3685. doi:10.1158/1538-7445.AM2014-3685

Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFR1-4) and activating downstream signaling pathways. FGF signaling has been demonstrated to be altered in a high proportion of cancers, with activating mutations and/or overexpression of FGFRs frequently observed in lung, gastric, breast and urothelial tumors. Therefore, targeting FGFRs using selective FGFR inhibitors is an attractive therapeutic approach to treat cancer patients. BAY 1163877 is as an orally available, selective and potent inhibitor of FGFR-1, -2 and -3 kinase activity. BAY 1163877 has been advanced through preclinical development and we disclose here the first details of its preclinical profile. BAY 1163877 inhibited FGFR-1, -2, -3 kinase activity in the nanomolar range and demonstrated a kinase selectivity profile for FGFR-1, -2 and -3 over 222 kinases tested. BAY 1163877 inhibited proliferation of various cancer cell lines in vitro and phosphorylation of downstream signaling molecules. BAY 1163877 was also tested in vivo in monotherapy and combination therapy on various human xenografts and syngeneic tumors and inhibited growth of tumors presenting at least one FGFR alteration.Overall, the in vitro and in vivo studies confirm that the FGFR inhibitor BAY 1163877 is a potent and selective inhibitor of altered FGFRs pathways in cancer models. A Phase 1 clinical trial (NCT01976741) has been initiated. Citation Format: Melanie Heroult, Peter Ellinghaus, Christian Sieg, Dirk Brohm, Sylvia Gruenewald, Marie-Pierre Collin, Ulf Boemer, Mario Lobell, Walter Huebsch, Matthias Ocker, Stuart Ince, Andrea Haegebarth, Rolf Jautelat, Holger Hess-Stumpp, Michael Brands, Karl Ziegelbauer. Preclinical profile of BAY 1163877 - a selective pan-FGFR inhibitor in phase 1 clinical trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1739. doi:10.1158/1538-7445.AM2014-1739

The PI3K/AKT/mTOR pathway is frequently activated in human cancer. AKT, a central element in the pathway, is essential for tumor growth, proliferation, survival, invasion and metastasis. Activation of AKT is a key mechanism in resistance to chemo-, radio- and targeted therapies. Thus, AKT is considered an attractive drug target. Herein, we report on the preclinical profile and combinability of BAY 1125976, a potent, highly selective, allosteric AKT1/2 inhibitor, which is particularly effective in models with PI3K-AKT pathway aberrations. In biochemical assays, BAY 1125976 demonstrates equal potency against AKT1 and AKT2 in the low nanomolar range (IC50 ∼ 10 nM) while it displays weaker activity against AKT3 (IC50 ∼ 500 nM) and is inactive against ∼230 other protein/ lipid kinases (IC50 > 1 μM). Mechanistically, BAY 1125976 blocks AKT signalling by inhibiting the phosphorylation of AKT at both Thr308 and Ser473 (IC50 < 1 nM), as well as downstream phosphorylation of 4E-BP1 (IC50 < 50 nM). The strong inhibition of cellular p-AKT and downstream signalling translates to a broad inhibition of tumor cell proliferation in vitro. In particular, tumor cell lines carrying defects in the tumor suppressor PTEN, or oncogenic mutations in PIK3CA are most sensitive to BAY 1125976 treatment. Daily oral dosing of BAY 1125976 in human xenograft tumor models induces strong pharmacodynamic inhibition of AKT phosphorylation that correlates with drug exposure. In vivo, BAY 1125976 demonstrates dose-dependent anti-tumor efficacy in multiple xenograft tumor models of different histological types with PIK3CA mutations or PTEN deletions while being well tolerated. BAY 1125976 can be effectively combined with various anti-cancer therapies. In vitro combination profiling shows synergistic anti-proliferative effects with anti-hormonal therapeutics in breast and prostate cancer cell lines, which translates to enhanced anti-tumor efficacy with durable tumor regressions in vivo. Furthermore, in vivo combination of BAY 1125976 with external beam radiation results in strong additive to synergistic efficacy and significant tumor growth delay. Moreover, the combination of BAY 1125976 with the bone-targeting agent Radium 223 in a breast cancer bone metastasis model results in reduced tumor and metastases burden and increased necrotic and fibrotic bone area. In conclusion, BAY 1125976 is a highly selective, potent allosteric AKT1/2 inhibitor with strong in vitro and in vivo activity in tumor models with activated AKT signalling and strong synergistic activity in combination. Targeting AKT might also provide a promising strategy for overcoming chemo/radio-resistance and increasing radio-sensitization and radio-potentiation. Citation Format: Oliver Politz, Lars Baerfacker, Stuart Ince, William J. Scott, Roland Neuhaus, Ulf Boemer, Martin Michels, Dominik Mumberg, Franz von Nussbaum, Karl Ziegelbauer, Andrea Haegebarth. BAY 1125976, a highly selective and potent allosteric AKT1/2 inhibitor, for the treatment of cancers with aberrations in the PI3K-AKT-mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2050. doi:10.1158/1538-7445.AM2013-2050