The three main Conservative frontrunners have all ruled themselves out of the race even though the next election is nearly two years away.
That means the Tory candidate who takes on Mr Khan is likely to be an obscure local politician – or an outsider with no governing experience.
The Mayor's tenure has been highly controversial because of an epidemic of knife and moped crime in the capital.
But he is still seen as the frontrunner in the next election because of London's inbuilt Labour majority.
In a bid to produce a strong challenger, the Tories will select their candidate in the next couple of months, so he or she will have more than 18 months to build a public profile.
But plans to take on Mr Khan have been harmed by the withdrawal of a string of high-profile figures.
Today James Cleverly, the Tories' popular vice-chairman, said: "We will have a strong candidate who will beat weak, petulant, and disappointing Sadiq Khan in 2020 but it won’t be me."
Former Education Secretary Justine Greening pulled out of the contest last week, saying she was focussing on boosting social mobility across the UK.
And Ed Vaizey, another ex-minister tipped for the role, said he was "never planning" to compete for the Conservative nomination.
Kit Malthouse, deputy mayor under Boris Johnson and now a Justice Minister, told The Sun today he wouldn't run for the job.
The Tories' best-known MEP Syed Kamall has also ruled out a bid for the post, despite coming second to Zac Goldsmith in the race for the nomination last time.
Other senior figures – such as Boris' brother Jo and George Osborne – are seen as unlikely to put themselves forward.
Labour sources have accused the Tories of running scared of Mr Khan as big names refuse to put their careers on the line.
Wes Streeting, the MP for Ilford North, said: “This says everything you need to know about the Tories’ appalling record of cutting police funding in London and pushing for an extreme hard Brexit that is risking jobs and growth.”
The first officially declared Tory candidates are Kevin Davis, a former child actor and council boss, and London Assembly member Andrew Boff.
Shaun Bailey, who advised David Cameron in Number 10, is another possible contender who's highly rated by London Tories.
The party could also turn to a outsider with an interesting background but no experience in frontline politics.
Duwayne Brooks, the best friend of murdered teen Stephen Lawrence, is one possible candidate.
Pro-Brexit tycoon Richard Tice and tech entrepreneur Rohan Silva are also tipped as contenders.
And today Nimco Ali, an anti-FGM campaigner who's not even a Tory member, confirmed she is considering putting her hat in the ring.
The Conservative candidate is set to be chosen this September, with the next mayoral election scheduled for May 2020.
Mr Khan's approval ratings have slipped in recent months – but still stand at more than 50 per cent, suggesting he is on course to win easily.
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