Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate

Furber, Mark; Tiden, A.K.; Gardiner, Philip; Mete, Antonio; Ford, Rhonan; Millichip, Ian; Stein, Linda; Mather, A. N.; Kinchin, Elizabeth; Luckhurst, Christopher A.; Barber, Simon; Cage, Peter; Sanganee, Hitesh J.; Austin, Rupert P.; Chohan, Kamaldeep K.; Beri, Raj K.; Thong, Bob; Wallace, A.V.; Oreffo, Victor; Hutchinson, Ray; Harper, SJ; Debreczeni, J.; Breed, J.; Wissler, Lisa; Edman, K. A. P.

doi:10.1021/jm401705g

Cited by 44 publications

(49 citation statements)

References 19 publications

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“…The cathepsin off-targets of osimertinib (inhibitor 1 ), in particular CTSC, play critical roles in protein processing, specifically in the activation of immune-related serine proteases (Furber et al, 2014, Hamon et al, 2016). These off-targets were identified not only in human cancer cell lines, but also in liver tissue from mice treated with doses of osimertinib that match those used in the literature to block T790M-EGFR-driven tumor growth in xenograft models (Cross et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Niessen

Dix

Barbas

et al. 2017

Cell Chemical Biology

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Summary Patients with non-small cell lung cancer (NSCLC) that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR where the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may impact drug activity and safety.

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Section: Discussionmentioning

confidence: 99%

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Niessen

Dix

Barbas

et al. 2017

Cell Chemical Biology

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“…In order to fulfil these objectives, two potent DPP1 inhibitors known as AstraZeneca (AZs) 1 and 2 were chosen as tool compounds. AZ1 and AZ2 had previously been identified as lead compounds in a DPP1 drug development programme within AstraZeneca (Furber et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

Gardiner

Wikell

Clifton

et al. 2016

British J Pharmacology

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Background and PurposeNeutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model.Experimental ApproachRats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response.Key ResultsMaximum NSP inhibition was achieved after 8 days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4–6 days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20 days in human.Conclusions and ImplicationsFollowing inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.

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“…LCMS: 423.30 (100%), 424.30 (23.8%), 421.29 (4.7%), 425.30 (2.5%), 422.29 (0.9%). 1 4.08 (dt, 1H, J = 5.9, 12.1), 4.48 (dd, 1H, J = 3.7, 9.9), 5.11 (t, 1H, J = 7.9), 7.31 (d, 1H, J = 8.9), 7.40 (m, 4H), 7.63 (d, 2H, J = 8.2). The spectrum shows 40 mol% of EtOH (which was the storage solvent): 13 C NMR (126 MHz, CD 3 OD) δ 170.…”

Section: Methodsmentioning

confidence: 99%

“…During the safety evaluation of AZD5248, aortic binding was observed in the quantitative whole‐body autoradiography (QWBA) and binding to elastin was suspected to be the cause . Elastin can be found in relatively high abundance in the aorta and has been demonstrated to interact with rofecoxib .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2 C‐14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole

Kingston

Bergare

Lönn

et al. 2017

Labelled Comp Radiopharmac

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In support of the development of a new treatment for COPD, 2 C-14 labeled compounds were required for in vitro animal studies. The synthesis of nitrile [ C]-1 was completed in 3 steps from C-14 labeled 4-bromobenzonitrile in accord with the previously developed medicinal chemistry route. The second compound, 2, did not possess an arylnitrile as did 1, which made the synthetic design more complex. An advanced, unlabeled benzotriazole containing intermediate, 10, was synthesized in low yield over 3 steps and was subsequently reacted with K CN to give a mixture of diastereomers 12. Separation of the diastereomers followed by deprotection afforded [ C]-2 in a 13% radiochemical yield.

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Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate

Abstract: A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.

Cited by 44 publications

References 19 publications

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity

Synthesis of 2 C‐14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole

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