Boris Johnson will warn the Tory leadership to protect the lowest paid as it reforms welfare amid growing calls for Chancellor George Osborne to rethink cuts to tax credits.
Millions of working households are expected to be left out of pocket as tax credits are slashed ahead of planned rises in the minimum wage and further cuts to the personal allowance.
In his final speech to Conservative Party Conference as London mayor, Mr Johnson is expected to tell activists they must use the election of Jeremy Corbyn as Labour leader to truly seize the mantle of the party which helps all people succeed.
But David Cameron has defended the cuts, insisting they are part of an overall package that "help make work pay" and claiming that some families will be £2,400 better off under the reforms.
The Prime Minister told BBC 2's Newsnight: "This was a package put together which I think in the long term does help make work pay, but also crucially reduces the cost of welfare so we can keep taxes down and afford to fund our National Health Service and our schools."
Meanwhile, Home Secretary Theresa May will use her speech to announce that the Government will stop European Union nationals from making asylum claims in the UK.
Over the last five years, the UK has received 551 claims from people from other member states like Poland and Spain, costing UK taxpayers £4.2 million, according to the Conservatives.
Mrs May said: "We will end this absurdity, saving public money and creating space in our asylum system to help more people who really need our protection.
"By taking a tougher approach to those who do not need our help, we can give more support to vulnerable people who are in real and urgent need of our protection."
The conference fringe has been dominated by discussion of who will succeed Mr Cameron as Tory leader, with Mr Johnson widely perceived as falling behind other rivals at the same time as the Chancellor cements his state as the firm favourite.
Speaking at the Manchester conference, the mayor is set to join Tory calls for a fresh look at tax credit changes. He is expected to say: "We must ensure that as we reform welfare and we cut taxes that we protect the hardest working and lowest paid.
"Shops workers, cleaners, the people who get up in the small hours or work through the night because they have dreams for what their families can achieve - the people without whom the London economy would simply collapse.
"(These are) the people Labour is leaving behind and then there is an even more important requirement. If people are to feel bound in to this system then there must be hope and aspiration, and above all there must be opportunity and it is here that we Tories have a massive advantage.
"Because if Labour is once again becoming the party that pointlessly bashes the rich it is we who give everyone the tools to make their own lives and their own successes."
Mr Johnson will appear alongside Zac Goldsmith, the Conservative candidate to replace him in City Hall at May's mayoral elections. He will tell activists how he believes the Richmond Park MP can conquer an insurgent left - insisting his two defeats of Ken Livingstone show the way to beating Mr Corbyn's energised left wing.
Tory delegates have faced a gauntlet of angry protests and abuse around the entrance to their Manchester conference since gathering on Sunday.
Mr Johnson will say: "I know these people, my friends. They are the London Labour Party - tankies and Trots with interesting vests and militants with vested interests.
"They are the people who idolise the late Hugo Chavez of Venezuela and believe the only problem with socialism is that it has never been properly tried.
"I know them because we have fought and beaten them twice and the reason I first wanted to get into that fight eight years ago is that I am fundamentally opposed to that style of politics."
Mr Johnson will say the left believes in "divide and rule" and adds: "Where there is a grievance, they foment it; where there is sectarianism, they take sides.
"Where there are racial or religious or ethnic divisions their instinct is always to accentuate and to Balkanise (divide a region into smaller mutually hostile states) and of course there is one conflict they relish above all others, and that is economic class war."
Mr Johnson's planned remarks on welfare reform will follow a growing row both inside and outside Tory ranks on tax credit cuts, which have already cleared the Commons.
Mr Osborne has rebuffed critics of cuts to tax credits, insisting it was failure to control public spending that would be "economic cruelty" for working families.
He hit back after David Davis joined Tory demands for a rethink, warning that the squeeze could prove as damaging to the party as the poll tax was under Margaret Thatcher.
The independent Institute for Fiscal Studies has warned that 13 million families will lose an average of £240 a year when the cuts come into effect in April, while three million will lose £1,000 or more.
Health Secretary Jeremy Hunt sparked fresh controversy when he told a fringe meeting tax credit cuts are a "very important cultural signal" as Britain seeks to match the work ethic of Asian and American countries.