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Molecular and Cellular Biology, Genetics

Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition

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 and Susanta Samajdar
Leena K. Satyam
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Ramulu Poddutoori
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Subhendu Mukherjee
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Sivapriya Marappan
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Sreevalsam Gopinath
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Aravind Basavaraju
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Lakshmi Narayana Kaza
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Manoj Kumar Pothuganti
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Shilpa Nayak
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Nandish C
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Amith A
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Ravindra MV
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Dabbeeru Madhu Babu
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Nagaraju A
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Suraj Tgore
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Thomas Antony
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Chetan Pandit
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Murali Ramachandra
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Shekar Chelur
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Girish Daginakatte
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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Susanta Samajdar
AURIGENE DISCOVERY TECHNOLOGIES, Bangalore, India.
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DOI: 10.1158/1538-7445.AM2017-LB-317 Published July 2017
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Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

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

  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
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Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition
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 and Susanta Samajdar
Cancer Res July 1 2017 (77) (13 Supplement) LB-317; DOI: 10.1158/1538-7445.AM2017-LB-317

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Abstract LB-317: Identification of a novel preclinical candidate for CDK7 inhibition
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 and Susanta Samajdar
Cancer Res July 1 2017 (77) (13 Supplement) LB-317; DOI: 10.1158/1538-7445.AM2017-LB-317
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Cancer Research Online ISSN: 1538-7445
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