Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis‐Specific Serine/Threonine Kinase 2 (TSSK2)

Hawkinson, Jon E.; Sinville, Rondedrick; Mudaliar, Deepti; Shetty, Jagathpala; Ward, Timothy R.; Herr, John C.; Georg, Gunda I.

doi:10.1002/cmdc.201700503

Cited by 25 publications

(11 citation statements)

References 33 publications

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“…A second study by our group (Hao et al, 2004) (Li et al, 2011;Sosnik et al, 2009). In addition, our group and others have developed in vitro assays that have increased the understanding of the TSSKs' mode of regulation (Bucko-Justyna et al, 2005;Hawkinson et al, 2017;Jaleel et al, 2005;Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

TSSK3, a novel target for male contraception, is required for spermiogenesis

Nayyab

Gervasi

Tourzani

et al. 2021

Molecular Reproduction Devel

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We have previously shown that members of the family of testis-specific serine/ threonine kinases (TSSKs) are post-meiotically expressed in testicular germ cells and in mature sperm in mammals. The restricted post-meiotic expression of TSSKs as well as the importance of phosphorylation in signaling processes strongly suggest that TSSKs have an important role in germ cell differentiation and/or sperm function. This prediction has been supported by the reported sterile phenotype of the TSSK6 knock-out (KO) mice and of the double TSSK1/TSSK2 KO. The aim of this study was to develop KO mouse models of TSSK3 and to validate this kinase as a target for the development of a male contraceptive. We used CRISPR/Cas9 technology to generate the TSSK3 KO allele on B6D2F1 background mice. Male heterozygous pups were used to establish three independent TSSK3 KO lines. After natural mating of TSSK3 KO males, females that presented a plug (indicative of mating) were monitored for the following 24 days and no pregnancies or pups were found. Sperm numbers were drastically reduced in all three KO lines and, remarkably, round spermatids were detected in the cauda epididymis of KO mice. From the small population of sperm recovered, severe morphology defects were detected. Our results indicate an essential role of TSSK3 in spermiogenesis and support this kinase as a suitable candidate for the development of novel nonhormonal male contraceptives.

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Section: Discussionmentioning

confidence: 99%

TSSK3, a novel target for male contraception, is required for spermiogenesis

Nayyab

Gervasi

Tourzani

et al. 2021

Molecular Reproduction Devel

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“…To expand this knowledge, Hawkinson and colleagues applied a HTS screen of around 17,000 compounds using a mobility shift assay with recombinant TSSK2 and fluorescently labeled glycogen synthase (5-FAM-GS) as substrate in a 384-well plate format. These authors were able to identify two, highly potent series of ATP-site TSSK2 inhibitors with either a pyrrolopyrimidine or pyrimidine core [ 82 ]. Three pyrrolopyrimidine core compounds included in this study, with highest potency against TSSK2, had been reported to be also effective inhibitors of several other kinases including IGF-1.…”

Section: Tssk Kinases As Therapeutic Targets For Male Contraceptionmentioning

confidence: 99%

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Salicioni

Gervasi

Sosnik

et al. 2020

Biology of Reproduction

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Male contraception is a very active area of research. Several hormonal agents have entered clinical trials, while potential non-hormonal targets have been brought to light more recently and are at earlier stages of development. The general strategy is to target genes along the molecular pathways of sperm production, maturation, or function, and it is predicted that these novel approaches will hopefully lead to more selective male contraceptive compounds with a decreased side effect burden. Protein kinases are known to play a major role in signaling events associated with sperm differentiation and function. In this review, we focus our analysis on the testis-specific serine kinase (TSSK) protein family. We have previously shown that members of the family of TSSKs are postmeiotically expressed in male germ cells and in mature mammalian sperm. The restricted postmeiotic expression of TSSKs as well as the importance of phosphorylation in signaling processes strongly suggests that TSSKs have an important role in germ cell differentiation and/or sperm function. This prediction has been supported by the reported sterile phenotype of the Tssk6 knockout (KO) mice and of the double Tssk1 and Tssk2 KO mice and by the male subfertile phenotype observed in a Tssk4 KO mouse model. Summary Sentence The established role of TSSKs in spermiogenesis and in male fertility, together with their unique kinase features, strongly supports this family of protein kinases as a very promising drug discovery target for development of a non-hormonal male contraceptive.

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“…While trials of hormonal methods are successful, they come with side effects, such as weight gain, acne, mood changes and changes in libido (39,40). Previous studies demonstrate promising results in targeting TSSKs using kinase inhibitors and the potential application of TSSK allosteric inhibitors (15,41), thereby emphasizing not only the important role of this family of kinases in spermatogenesis, but also how they can be targeted pharmaceutically.…”

Section: Discussionmentioning

confidence: 99%

Role of testis‑specific serine kinase 1B in undiagnosed male infertility

et al. 2022

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Male infertility is a global problem affecting a considerable part of the male population. current guidelines and practices aimed at diagnosing the cause of this problem still have low diagnostic yield. as novel candidate genes for infertility emerge, their functional role needs to be investigated in patient populations. The present study aimed to investigate testis-specific serine kinase 1B (TSSK1B), which was discovered in a previously diagnosed patient. Sanger sequencing of the coding regions and exon borders of TSSK1B was performed in a cohort of 100 male Bulgarian patients with unresolved infertility causes. Missense mutations were discovered in 10% of patients and were associated with clinical data on sperm dysmorphology. Two previously unreported mutations were discovered, p.3d>n and p.52F>l. all mutations were scored via in silico predictors and protein modelling using AlphaFold2. The present findings indicated an association between TSSK1B mutations and asthenoteratozoospermia, with further missense mutations in patients with azoospermia and teratozoospermia. Mutations in TSSK1B may be a cause of undiagnosed cases of male infertility and should be considered when molecular diagnostics are warranted.

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Potent Pyrimidine and Pyrrolopyrimidine Inhibitors of Testis‐Specific Serine/Threonine Kinase 2 (TSSK2)

Cited by 25 publications

References 33 publications

TSSK3, a novel target for male contraception, is required for spermiogenesis

TSSK3, a novel target for male contraception, is required for spermiogenesis

Testis-specific serine kinase protein family in male fertility and as targets for non-hormonal male contraception†

Role of testis‑specific serine kinase 1B in undiagnosed male infertility

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