Alkynes remain one of the most versatile functional groups in the medicinal chemist's toolkit. The triple bond delivers a compact, linear, and metabolically robust framework that enhances lipophilicity, tightens binding geometry, and resists common metabolic oxidation pathways simultaneously.
In oncology this has been directly exploited. Acalabrutinib \(Calquence, AstraZeneca\), an FDA-approved second-generation BTK inhibitor for mantle cell lymphoma and CLL, uses an alkyne-containing warhead that reacts selectively with Cys481 on BTK. Compared with the acrylamide-bearing ibrutinib, it is a softer electrophile, reducing off-target cysteine reactivity and improving the tolerability profile in the clinic. The nitrile bioisostere relationship is worth flagging too. Alkynes and nitriles share linear geometry but differ in polarity and reactivity. A 2023 Oxford study showed terminal alkyne analogues of nirmatrelvir inhibit SARS-CoV-2 Mpro irreversibly via Cys145, while the nitrile parent reacts reversibly. The terminal position also remains open for further decoration, offering handles to tune selectivity and pharmacokinetics that the nitrile simply cannot. In targeted protein degradation, alkynes are proving equally valuable. An alkyne-containing scaffold underpinned PD-305, a subnanomolar PTPN2 PROTAC degrader with cancer immunotherapy applications. Separately, copper-catalysed A3 alkyne-amine-aldehyde couplings were used to generate chiral PROTAC linkers that degrade BRD4 in cells, reinforcing the alkyne's dual role as both synthetic handle and structural contributor Alkynes address persistent bottlenecks across programmes: sp2-heavy scaffolds gain rigidity and metabolic stability, covalent projects gain a tunable warhead alternative to acrylamides, and PROTAC linker libraries benefit from click-ready building blocks that accelerate SAR. As the covalent inhibitor space grows and degrader modalities demand more creative linker chemistry, the alkyne's moment is still arriving. Do you see the alkyne warhead gaining ground over the acrylamide as the default cysteine-targeting motif, or will selectivity concerns at scale continue to favour the softer electrophile? Explore our range of Alkyne building blocks using our advanced search tools at https://lnkd.in/eVbfw6Ua To read more, take a look at the following interesting papers: 1. Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine https://lnkd.in/e-Cn298i 2. Use of Aldehyde–Alkyne–Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers https://lnkd.in/eZ\_2H5ie