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  • 1
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    Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-317-LB-317
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-317-LB-317
    Abstract: Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacological modulation of CDK7 kinase activity is considered as an approach to treat cancer. Multiple series of covalent CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR based approach. These compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumor activity. We have now identified a pre-clinical candidate AU-BGB-002 which is highly potent in inhibiting CDK7 in biochemical as well as cellular assays while fully efficiently engaging the target. In a panel of kinases, AU-BGB-002 shows selectivity for CDK7. A panel of cell lines derived from a diverse set of indications are sensitive to AU-BGB-002. AU-BGB-002 exhibits excellent drug-like characteristics including solubility, permeability, metabolic stability and good oral bioavailability. When tested in a xenograft model, AU-BGB-002 treatment resulted in dose dependent tumor growth inhibition in AML xenograft model with tumor stasis at a dose of 10 mg/kg. Potent inhibiton of tumor growth was accompanied by complete target engagement and suppression of pS5RNAPII RNAPolII Ser5 phosphorylation in a parallel PK-PD study. Efficacy studies in additional xenograft models, advanced DMPK and toxicity studies are ongoing for this compound. In summary, we have identified a novel and selective CDK7 covalent inhibitor candidate with desirable drug-like properties that shows excellent efficacy in an AML xenograft model. Findings presented here support further development of AU-BGB-002 for the treatment of cancer. Citation Format: Leena K. Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Aravind Basavaraju, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Shilpa Nayak, Nandish C, Amith A, Ravindra MV, Dabbeeru Madhu Babu, Nagaraju A, Suraj Tgore, Thomas Antony, Chetan Pandit, Murali Ramachandra, Shekar Chelur, Girish Daginakatte, Susanta Samajdar. Identification of a novel preclinical candidate for CDK7 inhibition [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 LB-317. doi:10.1158/1538-7445.AM2017-LB-317
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-LB-317
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 2
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    Abstract 3070: Potent and selective inhibition of CDK7 by novel covalent inhibitors
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3070-3070
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3070-3070
    Abstract: Background: Phosphorylation of the RNA polymerase II (RNAPII) in C-terminal domain (CTD) by Cyclin-dependent kinase 7 (CDK7) is an important step in cellular transcription process. Hence pharmacological modulation of CDK7 kinase activity is considered as an interesting approach to treat cancers that critically dependent on transcription to maintain their oncogenic state. Experimental procedures: Multiple series of novel covalent CDK7 inhibitors were identified by SBDD approach based on the binding mode of known CDK7 inhibitors to find early hits. Iterative medicinal chemistry efforts were performed to identify several lead compounds by optimizing the initial hits to achieve good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile. Summary: Highly potent ATP competitive covalent inhibitors of CDK7 from two distinct chemical series were identified. They show time-dependent inhibition of CDK7 enzyme activity as a proof of covalent binding and exhibit potent anti-proliferative activity in cell lines derived from various tumor types. CDK7 modulation by these compounds was also confirmed by monitoring cellular pS5RNAPII levels. Representative compounds from each series showed very good selectivity profile in broad kinase (332) panel. Lead molecules were identified based on excellent drug-like properties (solubility, permeability and good oral bioavailability). Tolerability and efficacy studies in rodent xenograft models are ongoing with selected leads to test their impact on tumor growth inhibition and to determine therapeutic window by oral administration. Conclusion: We have identified novel and selective CDK7 covalent inhibitors from two distinct chemical series with optimized drug-like properties including oral bioavailability. These compounds are being evaluated for anti-tumor activity in mouse xenograft models. Citation Format: Leena Khare Satyam, Ramulu Poddutoori, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Raghuveer Ramachandra, Manoj Kumar Pothuganti, Shilpa S. Nayak, Nandish C, Chandranath Naik, Ravindra MV, Madhu B. Dabbeeru, Nagaraju A, Mahankali B, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Susanta Samajdar, Murali Ramachandra. Potent and selective inhibition of CDK7 by novel covalent inhibitors. [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 3070.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3070
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Abstract B165: Potent selective and orally bioavailable inhibition of CDK12 by novel covalent inhibitors
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B165-B165
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B165-B165
    Abstract: Background: Cyclin-dependent kinase 12 (CDK12) coordinately regulates the transcription, splicing, and alternative splicing of several large pre-mRNAs. Defective CDK12 kinase activity has been associated with genomic instability and downregulation of genes in the DNA damage response (DDR) pathway. In addition, CDK12 depletion impairs alternate splicing, a process being increasingly implicated in cancer progression. Associated with Cyclin K (CycK), CDK12 regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at S2 in the C-terminal domain (CTD). Considering its role in transcription and RNA processing to maintain genomic stability/integrity in cancer, CDK12 is emerging as a potential therapeutic target to treat cancer. Experimental Procedures: Potent and selective CDK12 inhibitors were identified from multiple series by iterative medicinal chemistry efforts and SAR-based approaches. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity, and desirable pharmacokinetic profile to achieve antitumor activity.Summary: Very potent and highly selective compounds were identified from two distinct chemical series that are highly potent in inhibiting CDK12 in biochemical assays. Proving their covalent mode of action, these orally exposed compounds demonstrated robust engagement of CDK12 in a cellular context. Several of these potent and selective CDK12 inhibitors showed potent antiproliferative activity in various cancer cell lines derived from different origin, accompanied by robust CDK12 engagement and inhibition of pS2 (RNAP II). Further optimization of potency and ADME properties of initial lead compounds is in progress. Tolerability and efficacy studies are ongoing with selected early leads to test their impact on tumor growth inhibition in xenograft models. Conclusion: We identified novel, selective, and orally bioavailable covalent inhibitors of CDK12 from multiple distinct series with desirable drug-like properties, which are being evaluated for antitumor activity in xenograft models. Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Venkateswarlu Kasturi, Sasirekha Sivakumar, Shilpa Nayak, Ravindra M V, Suraj Tgore, Amit Dhudashiya, Charamanna K B, Thomas Antony, Mahaboobi M, Sanjeev Giri, Girish C. Daginakatte, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar. Potent selective and orally bioavailable inhibition of CDK12 by novel covalent inhibitors [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 B165.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B165
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Abstract B164: Identification of a novel highly selective and orally bioavailable preclinical candidate for CDK7 covalent inhibition
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 1_Supplement ( 2018-01-01), p. B164-B164
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 1_Supplement ( 2018-01-01), p. B164-B164
    Abstract: Background: Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacologic modulation of CDK7 kinase activity is considered as an approach to treat cancer. Experimental Procedures: Multiple series of covalent CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR-based approach. These compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity, and desirable pharmacokinetic profile to achieve antitumor activity. Summary: We have now identified a highly selective and orally bioavailable covalent CDK7 inhibitor AU-002 as a preclinical candidate. AU-002 is highly potent in inhibiting CDK7 in biochemical assays with robust engagement of CDK7 in cellular context. In a broad panel of 372 kinases, AU-002 shows excellent selectivity for CDK7. AU-002 exhibits excellent drug-like characteristics including solubility, permeability, metabolic stability, and good oral bioavailability. Oral treatment of this compound in a xenograft model resulted in dose-dependent tumor growth inhibition in AML xenograft model and with complete tumor regression at well-tolerated doses. Potent inhibition of tumor growth was accompanied by complete target engagement and suppression of pS5RNAPII in a parallel PK-PD study. Efficacy studies in additional xenograft models, advanced DMPK, and toxicity studies are ongoing for this compound. Conclusion: We have identified a novel and highly selective CDK7 covalent inhibitor candidate with good oral bioavailability that shows excellent efficacy in an AML xenograft model. Findings presented here support further development of AU-002 for the treatment of cancer. Citation Format: Ramulu Poddutoori, Leena Khare Satyam, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Charamanna KB, Lakshmi Narayana Kaza, Manoj Kumar Pothuganti, Sujatha Rajagopalan, Sasirekha Sivakumar, Bharath E N, Aravind A B, Amith A, Ravindra M V, Suraj Tgore, Thomas Antony, Chetan Pandit, Shekar Chelur, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Identification of a novel highly selective and orally bioavailable preclinical candidate for CDK7 covalent inhibition [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 B164.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-17-B164
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
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  • 5
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    Abstract C190: Potent and selective inhibition of CDK7 by novel covalent inhibitors
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C190-C190
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C190-C190
    Abstract: Cyclin-dependent kinase 7 (CDK7) is an important constituent of the cellular transcriptional machinery, where it phosphorylates the C-terminal domain (CTD) of RNAP polymerase II (RNAPII). Because many tumor types are critically dependent on transcription for maintenance of their oncogenic state, pharmacological modulation of CDK7 kinase activity is considered as an approach to treat cancer. Multiple series of CDK7 inhibitors were identified by iterative medicinal chemistry efforts and SAR based approach. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumor activity. We have identified compounds from two distinct chemical series that are highly potent in inhibiting CDK7 in biochemical assays. These inhibitors demonstrate time-dependent inhibition of CDK7 indicating covalent nature of binding. The compounds showed potent anti-proliferative activity in cell lines derived from various tumor types and this was accompanied by CDK7 modulation in cells as monitored by pS5RNAPII levels. They have excellent drug-like characteristics including solubility, permeability, metabolic stability and good oral bioavailability. In a broad panel of kinases (332 kinase), selected compounds from both series showed good selectivity profile. Tolerability and efficacy studies are ongoing with selected early leads to test their impact on tumor growth inhibition in xenograft models. We have identified novel and selective CDK7 covalent inhibitors from two series with desirable drug-like properties, which are being evauated for anti-tumor activity in xenograft models. Citation Format: Ramulu Poddutoori, Leena K. Satyam, Girish Daginakatte, Subhendu Mukherjee, Sivapriya Marappan, Sreevalsam Gopinath, Raghuveer Ramachandra, Anirudha Lakshminarasimhan, Manoj Pothuganti, Shilpa Nayak, Nandish C, Chandranath Naik, Ravindra MV, Madhu Dabbeeru, Thomas Antony, Chetan Pandit, Murali Ramachandra, Shekar Chelur, Susanta Samajdar. Potent and selective inhibition of CDK7 by novel covalent inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C190.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-C190
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 6
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    Abstract C191: Efficacy of novel IRAK4 inhibitors in ABC-DLBCL and AML models
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C191-C191
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C191-C191
    Abstract: Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein kinases belonging to tyrosine-like kinase (TLK) family. The IRAK family consists of IRAK1, IRAK2, IRAK3 and IRAK4 out of which only IRAK1 and IRAK4 exhibit kinase activity. IRAKs function as mediators of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and play an important role in innate immune signaling. Recent studies have reported the occurrence of oncogenic mutations in MYD88 in 30% of activated B cell diffuse large B-cell lymphoma (ABC DLBCL) and 90% of Waldenstrom's macroglobulinemia (WM) leading to constitutive activation of the IRAK4 and NFkB pathway. Recent studies have also highlighted the association of dysregulated innate immune signaling with Myelodysplastic syndrome (MDS) and Acute Myeloid leukaemia (AML). TLRs and their associated signal transducers are frequently overexpressed and/or constitutively activated in MDS. Overexpression and activation of IRAK1 is observed in AML. Thus IRAKs are attractive therapeutic targets for treatment of tumors with altered innate immune signaling such as ABC DLBCL and AML. We have designed, synthesized and tested small molecule inhibitors of IRAK4 based on hits originating from Aurigene's compound library. We have identified a series of novel bicyclic heterocycles as potent inhibitors of IRAK-4 with moderate to very high selectivity (S35 score = 0.03) in a 329 kinase panel. Lead compounds were profiled in proliferation and mechanistic assays (p-IRAK1 and p-TAK1 inhibition) in appropriate ABC DLBCL/AML cell lines. Aurigene lead compounds demonstrate potent inhibition of cellular proliferation with a good correlation to inhibition of phosphorylation of signaling intermediates in mechanistic assays. Lead compounds exhibit excellent PK profile and good oral bioavailability in mice. Preliminary in-vitro toxicology studies indicate a clean safety profile. Selected compounds demonstrate excellent in-vivo efficacy in relevant tumor models with & gt;90% tumor growth inhibition and good in-vivo PD modulation. In summary, a series of potent and selective IRAK4 inhibitors have been discovered and are being evaluated for treatment of cancers with dysregulated innate immune signaling. Citation Format: Venkateshwar Rao, Wesley Roy Balasubramanian, Kavitha Nellore, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra. Efficacy of novel IRAK4 inhibitors in ABC-DLBCL and AML models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C191.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-C191
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
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  • 7
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    Abstract 2384: Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2384-2384
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2384-2384
    Abstract: Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes such as DNA damage response, splicing and pre-mRNA processing. In association with Cyclin K (CycK), CDK12 regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at Serine 2 in the C-terminal domain (CTD). Overexpression of CDK12 in various tumor types suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. Considering its critical role in transcription and RNA processing CDK12 is emerging as a potential therapeutic target for cancer. Multiple series of potent and selective CDK12 covalent inhibitors were identified by iterative medicinal chemistry efforts and SAR-based approaches. Early compounds were optimized towards attaining good physicochemical properties, high potency, good selectivity and desirable pharmacokinetic profile to achieve anti-tumour activity. Very potent and highly selective CDK12 inhibitors have been identified from two distinct chemical series. The covalent mode of action for these biochemically potent compounds has been confirmed by CDK12 target engagement assay in the cellular context. These selective inhibitors showed significant anti-proliferative activity in TNBC and other cancer cell lines, which correlated with inhibition of pS2 (RNAP II), a bonafide CDK12 substrate and target engagement. In vivo target engagement, PD and efficacy data for optimized compounds with good oral bioavailability in a TNBC (HCC-70) xenograft model along with will be presented. Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D S, Sasirekha Sivakumar, Shilpa S. Nayak, Ravindra M. V, Hadianawala Murtuza, Devaraja T. S, Srinivas Kondela, Suraj Tgore, Amit A. Dhudashiya, Charamanna K. B, Thomas Antony, Girish Daginakatte, Sanjeev Giri, Shekar Chelur, Murali Ramachandra, Chetan Pandit, Susanta Samajdar. Preclinical evaluation of PD and efficacy of novel potent selective and orally bioavailable CDK12 covalent inhibitors in TNBC model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2384.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2384
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract 4798: Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4798-4798
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4798-4798
    Abstract: Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein kinases belonging to the tyrosine-like kinase (TLK) family. IRAKs function as mediators of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and play an important role in innate immune signaling. TLR/IL-1R stimulation leads to recruitment of MYD88, an adaptor molecule, to the activated receptor complex, which then complexes with IRAK4 and activates IRAK1. TRAF6 is then activated by IRAK1 leading to NFkB activation. Recent studies have reported the occurrence of gain of function oncogenic mutation (L265P) in MYD88 in ∼30% of activated B cell diffuse large B-cell lymphoma(ABC DLBCL) and ∼90% of Waldenstrom's macroglobulinemia (WM) leading to constitutive activation of IRAK4 and NFkB pathway. Among the DLBCL subtypes (GCB, ABC DLBCL and PMBL), ABC DLBCL is the most refractory. Inhibition of constitutive IRAK4 signalling can be used as a therapeutic strategy to treat ABC DLBCL Small molecule inhibitors of IRAK4 were synthesized based on hits originating from Aurigene's compound library. Structure guided drug design approach was used to further improve the potency. Lead compounds demonstrated moderate to very high selectivity towardsIRAK4 (S35 score of 0.03) when screened against a large panel of 329 kinases. Aurigene's lead compounds have excellent PK profile and good oral bioavailability in mice, leading to good in-vivo activity in TLR4 induced cytokine release model. Selected lead compounds were tested in a OCI-Ly3 xenograft model, which has a MYD88(L265P) mutation leading to constitutive activation of IRAK4 signaling. An advanced lead compound has demonstrated excellent efficacy in OCI-Ly3 model, with tumor stasis at low doses and tumor regression at higher doses. The compound is well tolerated and has a good therapeutic window as determined in a 14 day rodent toxicity study. In summary, a selective IRAK4 inhibitor has been identified with excellent efficacy and good safety profile. Citation Format: Wesley Roy Balasubramanian, Venkateshwar Rao Gummadi, Kavitha Nellore, Subhendu Mukherjee, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra. Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL. [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 4798.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4798
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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