Christian Fritz

Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

The Hsp90 chaperone is a master regulator of the stability and activity of multiple oncoproteins such as Her2, Akt, Bcr-Abl, c-Kit, EGFR and mutant BRAF. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach. There are now 14 drug candidates that target Hsp90 undergoing clinical trials in multiple indications as single agents or combination therapy. These compounds represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design. Although the compounds fall into distinct classes with unique properties, each inhibitor binds in the N-terminal ATP pocket and accumulates in tumor tissue while being rapidly cleared from circulation and normal tissue. The most advanced candidates are now in Phase 2 clinical trials and defining the therapeutic window, dosing schedule, and indication are the primary challenges for these potential first-in-class inhibitors.

IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells

BackgroundInhibitors of heat shock protein (Hsp) 90 induce apoptosis in multiple myeloma (MM) cells, but the molecular mechanisms underlying this cytotoxic outcome are not clear. Here, we investigate the effect of IPI-504, a novel and highly soluble inhibitor of the Hsp90 ATPase activity, on the unfolded protein response (UPR) in MM cells. The UPR is a stress response pathway triggered by sensors located at the endoplasmic reticulum (ER) membrane whose function is to reduce an excessive accumulation of misfolded protein in the ER. During normal development of B-lymphocytes to antibody-producing plasma cells, a partial UPR has been described, where IREα and ATF-6 are stimulated, whereas the third sensor, PERK, is not induced.MethodsLevels of the activated forms of the three main UPR sensors ATF-6, XBP-1 and PERK/eIF-2 were monitored in two different MM cells lines and one non-MM cell lines under various experimental conditions including incubation with increasing concentration of IPI-504. Also, MM cells were incubated with IPI-504 and several apoptosis markers were monitored.ResultsWe show here that a partial UPR is constitutively activated in plasma cell-derived MM cells and that IPI-504 can potently inhibit this pathway. IPI-504 achieves this by inactivating the transcription factors XBP1 and ATF6. In addition, IPI-504 also blocks the tunicamycin-induced phosphorylation of eIF2 by PERK. Dose-response and time course experiments reveal that IPI-504’s inhibitory effect on the UPR parallels its cytotoxic and pro-apoptotic effects on MM cells.ConclusionThe results presented here suggest that the IPI-504-induced apoptosis might be, in part, mediated by the inhibition of the partial UPR. Other malignancies that rely on intact and efficient UPR to survive could be considered as new indications for Hsp90 inhibitors.

Hsp90 (Heat Shock Protein 90) Inhibitor Occupancy Is a Direct Determinant of Client Protein Degradation and Tumor Growth Arrest in Vivo

Several Hsp90 (heat shock protein 90) inhibitors are currently under clinical evaluation as anticancer agents. However, the correlation between the duration and magnitude of Hsp90 inhibition and the downstream effects on client protein degradation and cancer cell growth inhibition has not been thoroughly investigated. To investigate the relationship between Hsp90 inhibition and cellular effects, we developed a method that measures drug occupancy on Hsp90 after treatment with the Hsp90 inhibitor IPI-504 in living cells and in tumor xenografts. In cells, we find the level of Hsp90 occupancy to be directly correlated with cell growth inhibition. At the molecular level, the relationship between Hsp90 occupancy and Hsp90 client protein degradation was examined for different client proteins. For sensitive Hsp90 clients (e.g. HER2 (human epidermal growth factor receptor 2), client protein levels directly mirror Hsp90 occupancy at all time points after IPI-504 administration. For insensitive client proteins, we find that protein abundance matches Hsp90 occupancy only after prolonged incubation with drug. Additionally, we investigate the correlation between plasma pharmacokinetics (PK), tumor PK, pharmacodynamics (PD) (client protein degradation), tumor growth inhibition, and Hsp90 occupancy in a xenograft model of human cancer. Our results indicate Hsp90 occupancy to be a better predictor of PD than either plasma PK or tumor PK. In the nonsmall cell lung cancer xenograft model studied, a linear correlation between Hsp90 occupancy and tumor growth inhibition was found. This novel binding assay was evaluated both in vitro and in vivo and could be used as a pharmacodynamic readout in the clinic.

The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activity in vivo

IPI-504, a water-soluble ansamycin analogue currently being investigated in clinical trials, is a potent inhibitor of the protein chaperone heat shock protein 90 (Hsp90). Inhibition of Hsp90 by IPI-504 triggers the degradation of important oncogenic client proteins. In cells, the free base of IPI-504 hydroquinone exists in a dynamic redox equilibrium with its corresponding quinone (17-AAG); the hydroquinone form binding 50 times more tightly to Hsp90. It has been proposed recently that the NAD(P)H:quinone oxidoreductase NQO1 can produce the active hydroquinone and could be essential for the activity of IPI-504. Here, we have devised a method to directly measure the intracellular ratio of hydroquinone to quinone (HQ/Q) and have applied this measurement to correlate NQO1 enzyme abundance with HQ/Q ratio and cellular activity of IPI-504 in 30 cancer cell lines. Interestingly, the intracellular HQ/Q ratio was correlated with NQO1 levels only in a subset of cell lines and overall was poorly correlated with the growth inhibitory activity of IPI-504. Although artificial overexpression of NQO1 is able to increase the level of hydroquinone and cell sensitivity to IPI-504, it has little effect on the activity of 17-amino-17-demethoxy-geldanamycin, the major active metabolite of IPI-504. This finding could provide an explanation for the biological activity of IPI-504 in xenograft models of cell lines that are not sensitive to IPI-504 in vitro. Our results suggest that NQO1 activity is not a determinant of IPI-504 activity in vivo and, therefore, unlikely to become an important resistance mechanism to IPI-504 in the clinic. [Mol Cancer Ther 2009;8(12):3369–78]

Abstract 2827: Activity of the proprietary Hsp90 inhibitor IPI-493 in models of colorectal cancer correlates with RAS pathway activation

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Heat shock protein 90 (Hsp90) plays a role in regulating the stability of key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3, and HER2. Infinity is developing two drug candidates in its Hsp90 chaperone inhibitor program: IPI-504 (retaspimycin hydrochloride), an intravenously-administered small molecule, and IPI-493, which is administered orally. To investigate the activity of IPI-493 in colorectal cancer (CRC), we performed in vitro growth inhibition (GI) studies on a CRC cell line panel. IPI-493 demonstrated GI50s in the range of 10-100nM in cell lines harboring either kRAS or bRAF mutations. To explore the in vivo potency of IPI-493, several mutant bRAF, mutant kRAS, as well as a wild-type kRAS/bRAF xenograft models were developed. Administration of IPI-493 at 100 mg/kg three times weekly demonstrated dramatic effects in all of the mutant models tested, with tumor growth inhibition (TGI) values between 70 and 90% and regression in one mutant bRAF model. Importantly, when IPI-493 was evaluated in combination with irinotecan, the combination resulted in greater tumor regression than seen with either agent alone with complete regressions observed in 4 of 10 animals. Interestingly, in the wild-type kRAS/bRAF models, IPI-493 administration did not lead to tumor growth inhibition. These results suggest that activation of the MAPK pathway may predispose these cells to sensitivity to Hsp90 inhibition. To investigate the effect of IPI-493 on MAPK pathway activity, we performed pharmacodynamic analysis after a single dose of IPI-493 in multiple xenograft models differing in their RAF/RAS mutation status. In mutant bRAF models, pathway activity was high, and IPI-493 administration resulted in downregulation of the activity of both bRAF and MEK. In models containing no mutations in kRAS or bRAF, we detect low baseline levels of both p-bRAF and p-MEK and little effect of IPI-493 administration. When Ras pathway activity in all CRC xenografts was compared with IPI-493 efficacy, there was a clear correlation between pathway activation and tumor growth inhibition by IPI-493. Our finding that Ras pathway activation predisposes CRC cells to sensitivity to IPI-493 and our combination data with irinotecan provide a clear rationale for the evaluation of Hsp90 inhibitors in colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2011-2827

Abstract 4820: Selective CDK7 inhibitors suppress super enhancer-genes, induce massive apoptosis in acute myeloid leukemia and demonstrate durable in vivo efficacy

CDK7 acts bi-functionally as a CDK-activating kinase (CAK) controlling proliferation and as a transcriptional kinase phosphorylating the CTD-RNA Pol II, driving efficient transcriptional processes. CDK7 has recently emerged as an attractive gene control target in cancers addicted to oncogenic transcription factors, regulated by super-enhancers (SEs), (Kwiatkowski et al., 2014; Chipumuro et al., 2014; Christensen 2014; Wang 2015). Acute Myeloid Leukemias (AML) harbor a heterogeneous set of mutations resulting in an altered cell state and aberrant epigenetic and transcriptional control, yet lack targeted therapeutic options. Employing our SE-platform technology we reveal mechanistic insights underlying the vulnerability of AML to gene control modulation via selective CDK7 inhibition. We describe first-in-class CDK7 inhibitors that covalently target a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition. Several lead compounds exhibit significant biochemical potency (Ki = 10-60 nM and kinact = 5-13/h) and exquisite selectivity when profiled against >400 other kinases. In a cancer cell line panel, acute leukemias emerged among the most sensitive to CDK7 inhibition. Moreover, AML cell lines undergo rapid and robust apoptosis within 24 hours. This is preceded by CDK7 target engagement and concomitant loss of P-CTD-RNAPolII suggesting the primary consequence of CDK7 inhibition is the impaired transcriptional activity of CDK7. Further investigation of the transcriptional consequences of CDK7 inhibition point to a reliance on key disease relevant SE-genes (e.g. MYB, HOX10A and MYC) that are predominantly reduced. Given the covalent mechanism of our CDK7 inhibitors and PK profile in vivo, we use short treatments in vitro with subsequent washout of free drug to model intermittent dosing regimens in vivo. We demonstrate that short drug exposures maintain a robust irreversible apoptotic response in leukemia cells. In contrast, treated non-transformed cells recover from a transient G2/M arrest followed by re-synthesis of free CDK7 and no apoptosis/cell death. We have extended these findings to in vivo experiments whereby intermittent dosing in AML patient derived xenograft models (PDX) maintains efficacy (reducing human CD45+ leukemia cells to In summary, we describe first-in-class CDK7 inhibitors that are potent and selective and lead to durable, complete responses in PDX models of AML. These data support the rationale for advancing one or more members of this class of compounds toward clinical development. Citation Format: Shanhu Hu, Nan Ke, Yixuan Ren, Jeremy Lopez, Sofija Miljovska, David Orlando, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz, Yoon Jong Choi. Selective CDK7 inhibitors suppress super enhancer-genes, induce massive apoptosis in acute myeloid leukemia and demonstrate durable in vivo efficacy. [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 4820.

Abstract 1511: AML patient clustering by super-enhancers reveals an RARA associated transcription factor signaling partner

Prior studies have shown that the RARA gene is associated with a super-enhancer (SE) and has upregulated mRNA expression in a subset of AML patients. Furthermore, this has been found to confer increased sensitivity to SY-1425, a potent and selective RARα agonist. We sought to better characterize the cell state and transcription factor circuitry in these RARA-high AML cells. Clustering of 62 primary AML patient samples based on their genome wide SE maps identified six discrete clusters. RARA-high patients partitioned principally into cluster 2, and to a lesser extent 1, suggesting that RARA upregulation is associated with a specific transcription factor (TF) network and cell state. To start unraveling the TF circuitry in the RARA-high cluster, we investigated which other TFs were SE associated with clusters 1 and 2. In particular, interferon regulatory factor 8 (IRF8) was found to be strongly associated with clusters 1 and 2 by SE and mRNA expression, similar to RARA. Moreover, the expression of both genes is correlated in primary patient samples. IRF8 is involved in interferon signaling and previous studies have shown crosstalk between interferon and retinoic acid signaling. Furthermore, aberrant IRF8 pathway signaling is implicated in AML and CML pathogenesis. The tight clustering of RARA and IRF8 in patient subgroups defined by genome wide enhancer maps suggests RARα and IRF8 may form an integrated transcriptional circuit. Indeed, treatment with SY-1425 was found to strongly induce interferon-like gene expression changes in AML cells with high RARA or IRF8 levels, including the tumor suppressive IFN responsive gene IRF1. While RARA-high AML cell line models have been previously shown to respond to SY-1425, we found that models with high IRF8 expression and low levels of RARA were also found to respond to SY-1425. Such IRF8-high, RARA-low AML cell lines showed activation of similar transcriptional pathways as RARA-high cell lines in response to SY-1425 based on GSEA. IRF8-high AML also had comparable low nM EC50 anti-proliferative effects following SY-1425 treatment. In addition, SY-1425 was found to elicit differentiation in both RARA-high and IRF8-high AML cell lines based on flow cytometry. While RARA and IRF8 expression appear correlated, this data suggests that IRF8 levels may predict for sensitivity to SY-1425 in addition to RARA levels, particularly in cases of AML with high IRF8 expression but low RARA levels. Insights derived from enhancer analysis, transcriptional profiling and differentiation response in preclinical models support the recently initiated Phase 2 trial of SY-1425 (NCT02807558) in which we are evaluating the SE based patient selection strategies and gene circuitry derived pharmacodynamics clinical measurements, including differentiation markers, in patients with AML and MDS. Citation Format: Michael R. McKeown, Matthew L. Eaton, Chris Fiore, Emily Lee, Katie Austgen, Darren Smith, M. Ryan Corces, Ravindra Majeti, Christian C. Fritz. AML patient clustering by super-enhancers reveals an RARA associated transcription factor signaling partner [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 1511. doi:10.1158/1538-7445.AM2017-1511

Abstract 3085: SY-1425 (tamibarotene), a selective RARα agonist, shows synergistic anti-tumor activity with hypomethylating agents in a biomarker selected subset of AML

In patients with acute myeloid leukemia (AML) (≥ 60 years) and myelodysplastic syndrome (MDS), the use of hypomethylating agents (HMAs) may extend survival, but cure rates are very low and new treatment approaches are needed. HMAs, such as azacitidine, work by inhibiting DNMT1, leading to depletion of DNA methylation in the tumor cells. Hypomethylation, in turn, leads to the re-expression of genes associated with differentiation and growth arrest. We have recently explored the potent and selective RARα agonist SY-1425 in a genomically defined subset of AML. SY-1425 binds to RARα and causes a transition from repression to strong activation of target genes, thus reprogramming the tumor cells toward terminal maturation in RARA-high AML models, supporting our recently initiated Phase 2 trial in a biomarker-selected subset of AML and MDS (NCT02807558). Based on potential mechanistic synergy, we evaluated SY-1425 in combination with HMAs and identified a synergistic anti-proliferative effect. In RARA-high AML cell lines, but not RARA-low, the combination of SY-1425 with either azacitidine or decitabine showed synergistic anti-proliferative effects on the cells, with combination indices less than 0.5 over a range of concentrations from 0.01 to 100nM of SY-1425 and 0.1 to 1µM of HMAs. SY-1425 and azacitidine were also co-administered to a disseminated patient-derived xenograft (PDX) mouse model of RARA-high AML. The combination demonstrated superior reduction of tumor burden vs either therapy alone, leading to deeper and more durable responses with less than 1% detectable tumor burden. A follow-up study in the RARA-high PDX model investigated different treatment schedules of SY-1425 and azacitidine over a period of 56 days, supporting a regimen that maximizes anti-tumor activity and tolerability. Mechanistic studies using RNA-seq and ChIP-seq in AML cell line models have revealed that while azacitidine had only moderate suppressive or activating effects over a broad set of genes, the addition of SY-1425 in RARA-high models resulted in strong and specific induction of genes bound by RARα. It is hypothesized that azacitidine acts to prime the tumor cells for reprogramming by SY-1425. The loss of methyl-cytosine residues following azacitidine treatment lowers the barrier to SY-1425 mediated gene induction. It was observed that the two agents work cooperatively to promote terminal differentiation and decrease proliferation of the AML tumor cells, with the potential for increased clinical benefit in a subset of AML defined by a RARA super-enhancer. Based on the largely non-overlapping clinical toxicity profiles of azacitidine and SY-1425, supported by the observed tolerability of the combination in preclinical models, these findings provide a strong rationale for a planned study of this combination in biomarker selected, newly diagnosed AML patients. Citation Format: Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian C. Fritz, Eric Olson. SY-1425 (tamibarotene), a selective RARα agonist, shows synergistic anti-tumor activity with hypomethylating agents in a biomarker selected subset of AML [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 3085. doi:10.1158/1538-7445.AM2017-3085

Abstract P6-11-18: A novel subgroup of estrogen receptor positive breast cancer may benefit from super-enhancer guided patient selection for retinoic acid receptor α agonist treatment

Endocrine-resistance remains a major challenge for treatment of breast cancer. Multiple mechanisms for endocrine resistance have been proposed, including altered expression of ER co-regulators such as Retinoic Acid Receptor Alpha (RARα). Furthermore, crosstalk between estradiol and RA signaling is known and upregulation of RARα has been observed in tamoxifen resistance. We propose a novel treatment paradigm for a newly-defined subset of HR+ patients based on our discovery of a super-enhancer (SE) associated with the RARA locus. SEs are large, highly active chromatin regions that pinpoint cancer vulnerabilities. The RARA SE-identified vulnerability can be targeted using the potent, selective, and metabolically stable RARα agonist SY-1425 (tamibarotene). SY-1425 is approved in Japan to treat Acute Promyelocytic Leukemia, has a well-established efficacy and safety profile, and may enhance response to hormonal therapy (HT) in this newly-defined subset of HR+ patients potentially delaying the need for alternate treatment. Tumor samples from 42 breast cancer patients were analyzed across a range of molecular subtypes. We identified an SE linked to the RARA gene in 54.5% of the hormone positive patient samples. RARA SEs predicted sensitivity to SY-1425 in 12 breast cancer cell lines confirming their functional role, and showed a correlation with RARA gene expression. A panel of 37 breast cancer cell lines was tested for SY-1425 anti-proliferative activity and gene expression levels, and identified RARA as the single best predictor of response. Proliferation of RARA-high cells was inhibited by SY-1425 with low nanomolar EC50s. Transcriptional profiling was performed on 4 HR+ and 3 HER2+/HR- breast cancer cell lines and analyzed by GSEA to examine the molecular response to SY-1425. Signatures for growth including E2F, MYC, DNA replication, and cell cycle were significantly downregulated while retinol metabolism and luminal signaling were upregulated. Estrogen signaling was also significantly altered by SY-1425, supporting known crosstalk between RARα and ER. Consistent with differentiation, CYP26A1 and VE-Cadherin were induced and Actin and Ki67 were diminished at relevant concentrations of SY-1425 and could serve as pharmacodynamic markers of response. To test responses to SY-1425 in vivo , two cell line-derived models and two patient-derived breast cancer models (one RARA-high, and one RARA-low each) were treated with SY-1425. SY-1425 inhibited tumor growth in the RARA-high models, but not the RARA-low models (43% versus 0% TGI). Consistent with the observed changes in transcription, SY-1425 in combination with tamoxifen synergistically inhibited proliferation of RARA-high breast cancer cell lines. Although a few clinical studies have investigated the use of ATRA in HR+ breast cancer without success, our results suggest that patient selection based on the RARA SE may predict which HR+ breast cancer patients could derive benefit by adding an RARα agonist to HT. The potential to prolong or increase the clinical effect of anti-estrogen therapy with SY-1425, which has improved potency, selectivity, and PK stability versus ATRA, would be an attractive strategy to explore. Citation Format: McKeown MR, Fiore C, Lee E, Eaton ML, Orlando D, Guenther MG, Collins C, Chen MW, Fritz CC, di Tomaso E. A novel subgroup of estrogen receptor positive breast cancer may benefit from super-enhancer guided patient selection for retinoic acid receptor α agonist treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-18.

Abstract 1151: SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors

CDK7 has recently emerged as an attractive target in cancer since its inhibition decreases the transcript levels of oncogenic transcription factors, especially those driven by super-enhancers (SEs). Cancers have been hypothesized to be addicted to SE regulated genes and simultaneous suppression of multiple SE associated genes through CDK7 inhibition might represent a novel, powerful way to selectively kill cancer cells. Previously, we reported that SY-1365, a highly selective covalent CDK7 inhibitor, induces apoptosis in leukemia cells, but not in non-malignant cells, and demonstrates anti-tumor activity in in vivo models of leukemia. In this study, we extend these findings to the identification of multiple solid tumors that are susceptible to SY-1365 and compare the effects of SY-1365 on gene expression to other gene control agents. SY-1365 was screened in a panel of solid tumor cell lines, revealing activity in breast, ovarian, colorectal and lung cancer cells with low nM EC50 and rapid induction of apoptosis. In breast cancer, a subset of triple negative breast cancer (TNBC) cell lines were found to be more sensitive than luminal breast cancer cell lines, so we extended our studies to in vivo models and showed substantial tumor growth inhibition in multiple patient-derived xenograft (PDX) models of TNBC. Since other compounds have been reported to modulate the expression of SE regulated genes, we compared the transcriptional effects of SY-1365 treatment with those of a pan-CDK inhibitor (flavopiridol), a CDK9 inhibitor (NVP2) and a BRD4 inhibitor (JQ1) using microarray analysis. Applying principal component analysis, we observed a unique transcriptional response elicited by SY-1365 compared to the other inhibitors. NVP2 and flavopiridol inhibited an overlapping and much larger gene set than either JQ1 or SY-1365. Interestingly, SY-1365 treatment decreased the expression of oncogenic transcription factors, cell cycle checkpoint regulators and DNA damage response genes. The downregulation of transcripts involved in apoptosis and DNA damage response by SY-1365 suggests that CDK7 inhibition might synergize with targeted agents that affect these processes. Indeed, we observed that SY-1365 was synergistic with the PARP inhibitor niraparib and the Bcl-2 inhibitor venetoclax in triple negative breast cancer and AML cell lines, respectively. In summary, we have identified TNBC, ovarian and small cell lung cancer cell lines as highly sensitive to SY-1365 in vitro and have observed substantial tumor growth inhibition in PDX models of TNBC. SY-1365 induced a distinct transcriptional response compared with other transcriptional inhibitors, with apoptotic and DNA damage pathways being central. Finally, these mechanism of action studies support a rationale for investigating combinations of SY-1365 with inhibitors of PARP and Bcl-2. Citation Format: Shanhu Hu, Nan Ke, Yixuan Ren, Sofija Miljovska, Nisha Rajagopal, Michael McKeown, David Orlando, Kevin Sprott, Yoon J. Choi, Eric Olson, Christian C. Fritz. SY-1365, a potent and selective CDK7 inhibitor, exhibits promising anti-tumor activity in multiple preclinical models of aggressive solid tumors [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 1151. doi:10.1158/1538-7445.AM2017-1151